Phenylindoles for the treatment of HIV

ABSTRACT

The invention as disclosed herein is a method and composition for the treatment of HIV in humans and other host animals, that includes the administration of an effective HIV treatment amount of a phenylindole as described herein or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier. The compounds of this invention either possess antiviral (i.e., anti-HIV) activity, or are metabolized to a compound that exhibits such activity.

FIELD OF THE INVENTION

[0001] This invention is in the area of phenylindoles that are usefulfor the treatment of HIV infection, and, in particular, phenylindolesthat exhibit significant activity against resistant strains of HIV.

[0002] This application claims priority to U.S. Provisional ApplicationNo. 60/283,393, filed on Apr. 11, 2001.

BACKGROUND OF THE INVENTION

[0003] In 1983, the etiological cause of AIDS was determined to be thehuman immunodeficiency virus (HIV). Numerous compounds have since beensynthesized to combat the virus, designed to inhibit progression beyondvarious stages of the virus's lifecycle. A focal point in AIDS researchefforts has been the development of inhibitors of human immunodeficiencyvirus (HIV-1) reverse transcriptase (RT), an enzyme responsible for thereverse transcription of the retroviral RNA to proviral DNA (Greene, W.C., New England Journal of Medicine, 1991, 324, 308-317; Mitsuya, H. etal., Science, 1990, 249, 1533-1544; De Clercq, E., J. Acquired ImmuneDefic. Syndr. Res. Human. Retrovirus, 1992, 8, 119-134). Promisinginhibitors include normucleoside inhibitors (NNI), which bind to aspecific allosteric site of HIV-1 RT near the polymerase site andinterfere with reverse transcription by altering either the conformationor mobility of RT, thereby leading to noncompetitive inhibition of theenzyme (Kohlstaedt, L. A. et al., Science, 1992, 256, 1783-1790).

[0004] Several classes of compounds have been identified as NNI of HIV-1RT. Examples include the following:

[0005] (a) 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymines (HEPT;Tanaka, H. et al., J.

[0006] Med. Chem., 1991, 34, 349-357; Pontikis, R. et al., J. Med.Chem., 1997, 40, 1845-1854; Danel, K., et al., J. Med. Chem., 1996, 39,2427-2431; Baba, M., et al., Antiviral Res, 1992, 17, 245-264);

[0007] (b) bis(heteroaryl)piperazines (BHAP; Romero, D. L. et al., J.Med. Chem., 1993, 36, 1505-1508);

[0008] (c) dihydroalkoxybenzyloxopyrimidine (DABO; Danel, K. et al.,Acta Chemica Scandinavica, 1997, 51, 426-430; Mai, A. et al., J. Med.Chem., 1997, 40, 1447-1454);

[0009] (d)2′-5′-bis-O-(tertbutyldimethylsilyl)-3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″, 2″-dioxide) pyrimidines (TSAO; Balzarini, J. et al.,Proc. Natl. Acad. Sci. USA, 1992, 89, 4392-4396);

[0010] (e) phenethylthiazolylthiourea (PETT) derivatives (Bell, F. W. etal., J. Med. Chem., 1995, 38, 4929-4936; Cantrell, A. S. et al., J. Med.Chem., 1996, 39, 4261-4274);

[0011] (f) tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2 (1H)-oneand -thione (TIBO) derivatives (Pauwels, R. et al. Nature, 1990, 343,470-474);

[0012] (g) alpha-anilinophenylacetamide (alpha-APA) derivatives(Pauwels, R. et al. Proceedings of the National Academy of Sciences USA,1993, 90, 1711-1715); and

[0013] (h) indole derivatives (Williams et al., U.S. Pat. No. 5,527,819(Jun. 18, 1996); and its counterpart PCT application PCT/US94/01694,published as WO 94/19321 on Sep. 1, 1994).

[0014] The indole derivatives identified by Williams et al., assigned toMerck & Co., in U.S. Pat. No. 5,527,819 received particular interestbecause of their ability to potently inhibit HIV reverse transcriptase.A number of these compounds displayed EC₉₀s against HIV reversetranscriptase at concentrations as low as 2 micromolar. However, thiswork was not pursued, perhaps because HIV virus that had been exposed toother drugs was shown to be cross resistant to these indoles (Williams_(et al.) , Journal of Medicinal Chemistry, 1993, 36(9), 1291-94).

[0015] The class of compounds disclosed in the '819 patent encompasses alarge class of compounds represented generally by the following broadstructural formula:

[0016] in which the variables X, Y, Z, R and R⁶ were broadly defined toencompass a plethora of compound_(S). The patent presented examples fornearly one hundred of the compounds encompassed by the structure, andincluded several examples in which Z was —C(O)NH₂, Y was SO₂ and R wasphenyl or substituted phenyl.

[0017] U.S. Pat. No. 5,124,327, issued Jun. 23, 1992 to Greenlee et al.and assigned to Merck disclosed a class of compounds of the generalformula above, in which X is H, R⁶ is H, Y is S, and R is phenyl. Thepatent disclosed that the compounds act as reverse transcriptaseinhibitors.

[0018] Indoles have been used for the treatment of a variety of diseasesother than HIV. For example, Farina et al., in U.S. Pat. No. 5,981,525(Nov. 9, 1999), disclose a complex array of indoles that are useful forthe treatment of osteoporosis, because they reduce bone resorption byinhibiting osteoclast H⁺-ATPase.

[0019] U.S. Pat. No. 6,025,390, granted Feb. 15, 2000 to Farina et al.,discloses another complex array of indole derivatives, referred to asheteroaromatic pentadienoic acid derivatives, and again suggest theiruse for the treatment of osteoporosis.

[0020] U.S. Pat. No. 5,489,685, granted Feb. 6, 1996, Houpis et al.discloses a similar set of compounds in the furo(2,3-B) pyridinecarboxylic acid ester class, and specifically suggest their use for thetreatment of HIV.

[0021] U.S. Pat. No. 5,945,440 to Kleinschroth et al. discloses a classof indolocarbazole amides, and proposes their use for a variety ofdiseases including cancer, viral diseases (including HIV), heart andblood vessel diseases, bronchopulmonary diseases, degenerative diseasesof the central nervous system, inflammatory disorders, and otherdiseases.

[0022] Gunasekera et al., in U.S. Pat. No. 4,866,084 (Sep. 12, 1989),disclose a class of bisindole alkaloid compounds, and state that thecompounds are useful as antiviral and antitumor agents. The patent alsodescribes the compounds' activity against HSV (herpes simplex virus).

[0023] Matsunaga et al., in U.S. Pat. No. 5,852,011 (Dec. 22, 1998),disclose a class of indole derivates substituted by a heteroarylfunction and an amide function. The compounds are said to possessantitumor, antiviral, and antimicrobial properties.

[0024] Dykstra et al., in U.S. Pat. No. 5,935,982 disclose a class ofbis-indoles and specifically propose their use for treating retroviralinfections, and especially infection by HIV.

[0025] Domagala et al., in U.S. Pat. No. 5,929,114 (Jul. 27, 1999)disclose a class of arylthio and bithiobisarylamide compounds thatreportedly have antibacterial and antiviral activity. The invention issaid to encompass indole derivatives as well.

[0026] Pevear et al., in U.S. Pat. No. 5,830,894 (Nov. 3, 1998) disclosea class of triazinoindole derivatives that reportedly have pestivirusactivity, most notably BVDV activity.

[0027] It is known that over a period of time, antiviral agents that areactive against HIV =induce mutations in the virus that reduce theefficacy of the drug. This was apparently the problem exhibited by theMerck indoles in U.S. Pat. No. 5,527,819 (Williams et al, Journal ofMedicinal Chemistry, 1993, 36(9), 1291-94). Drug resistance mosttypically occurs by mutation of a gene that encodes for an enzyme usedin viral replication, and most typically in the case of HIV, reversetranscriptase, protease, or DNA integrase. It has been demonstrated thatthe efficacy of a drug against HIV infection can be prolonged,augmented, or restored by administering the compound in combination oralternation with a second, and perhaps third, antiviral compound thatinduces a different mutation from that caused by the principle drug.Alternatively, the pharmacokinetics, biodistribution, or otherparameters of a drug can be altered by such combination or alternationtherapy. In general, combination therapy is typically preferred overalternation therapy since combination therapy induces multiplesimultaneous pressures on the virus. However, one cannot predict whichmutations will be induced in the HIV-1 genome by a given drug, whetherthe mutations are permanent or transient, or how an infected cell with amutated HIV-1 sequence will respond to therapy with other agents incombination or alternation. These factors are exacerbated by the factthat there is a paucity of data on the kinetics of drug resistance inlong-term cell cultures treated with modem antiretroviral agents.

[0028] Therefore, there is a need to improve the duration of antiviralefficacy produced by antiretroviral drugs, and to provide antiviraldrugs that are effective against strains of the virus that havedeveloped cross resistance through mutational adaptation. Further,although many of the non-nucleotide reverse transcriptase inhibitors(NNRTI) in the prior art exhibit favorable pharmacokinetic andbiodistribution profiles, there remains a need to improve upon theseparameters.

[0029] It is an object of the present invention to provide new compoundsfor the treatment of patients infected with HIV. There is a special needto provide new compositions and methods for the treatment of patientsinfected with HIV that exhibit significant activity againstdrug-resistant forms of the virus.

SUMMARY OF THE INVENTION

[0030] A novel class of phenylindoles has been discovered that displaysignificant antiviral activity against HIV, and in particular, strainsof the HIV that have developed cross resistance to other anti-HIV drugs.It has surprisingly been discovered that HIV activity can be enhanced,and in certain cases cross resistance can be substantially overcome, byincorporating into the molecule at least two moieties other thanhydrogen on either the phenyl ring or the benzyl ring of the indolefunction, or on both rings. The substituents are preferably contained atthe 3″ and 5″ positions if located on phenyl ring, and at the 4′ and 5′;5′ and 6′ or the 5′ and 7′ positions if located on the benzyl ring ofthe indole function. Methyl is a preferred group for substitution on thephenyl ring. Preferred substituents for the benzyl ring of the indolefunction are small moieties, and include substituents such as chlorine,fluorine, bromine, CF₃, vinyl bromide and NO₂.

[0031] In one embodiment of the present invention, the compound can berepresented generally by the following chemical formula:

[0032] or its pharmaceutically acceptable salt or prodrug, wherein

[0033] (a) R¹ is hydrogen; acyl; —C(═O)H; —C(═W)H; —C(═O)R²; —C(═W)R²;—C(═O)OH; —C(═W)OH; —C(═O)OR²; —C(═W)OR²; —C(═O)SH; —C(═W)SH; —C(═O)SR²;—C(═W)SR²; —C(═O)NH₂; —C(═W)NH₂; —C(═O)NHR²; —C(═W)NHR²; —C(═O)NR2RW;—C(═W)NR²R³; —C(═W)NH—(CH₂)_(p)-(amino acid) or —(CH₂)_(p)-(amino acid);

[0034] (b) R^(4′), R^(5′), R^(6′), R^(7′), R^(2″), R^(3″), R^(4″),R^(5″) and R^(6″) are each independently H; halo (F, Cl, Br or I); —NO₂;—CN; —OH; —OR²; —SH; —SR²; —NH₂; —NHR²; —NR²R³; —NHSO₂—C₁₋₃alkyl;—NR²SO₂—C₁₋₃alkyl; —NHCO—C₁₋₃alkyl; —NR²CO—C₁₋₃alkyl; optionallysubstituted or unsubstituted branched or unbranched alkyl, alkenyl oralkynyl (such as an optionally substituted or unsubstituted branched orunbranched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, and in particular CH₃,CF₃, vinyl bromide, —CR²R²—S(O)_(n)—R³, —CR²R²NH₂, —CR²R²NHR²,—CR²R²NR²R³ and —CR²R²—C(═O)R²); alkacyl; optionally substituted orunsubstituted acyl; —C(═O)H; —C(═W)H; —C(═O)R²; —C(═W)R²; —C(═O)OH;—C(═W)OH; —C(═O)OR²; —C(═W)OR²; —C(═O)—SH; —C(═W)SH; —C(═O)SR²;—C(═W)SR²; —C(═O)NH₂; —C(═W)NH₂; —C(═O)NHR²; —C(—W)NHR2; —C(═O)NR²R³;—C(═W)—NR²R³, —C(═W)NH(CH₂)_(p)-(amino acid), a residue of an amino acidor —(CH₂)_(p)(amino acid); wherein if R^(5′) is hydrogen, F, Cl, Br,—NO₂, —CN, —OR², —NR²R², —NHSO₂—C₁₋₃alkyl or —NHCO—C₁₋₃alkyl, then atleast one of R^(4′), R^(6′) and R^(7′) is not hydrogen or alternatively,wherein at least two of R^(4′), R^(5′), R^(6′), R^(7′) are not hydrogen.

[0035] (c) Z is optionally substituted or unsubstituted acyl, —C(═O)NH₂;—C(═W)—NH₂; —C(═O)NHR²; —C(═W)NHR²; —C(═O)NR²R³; —C(═W)NR²R³;—C(═W)NH(CH₂)_(p)-(amino acid); a residue of an amino acid,—(CH₂)_(p)-(amino acid); —C(═O)R³; —C(═O)H; —C(═W)H; —C(═O)R²; —C(═W)R²;—C(═O)OR³; —C(═O)OH; —C(—W)OH; —C(═O)OR2; —C(—W)—OR²; —C(═O)— SH;—C(═W)SH; —C(═O)SR²; —C(═W)SR²; optionally substituted or unsubstitutedbranched or unbranched alkyl, alkenyl or alkynyl (such as an optionallysubstituted or unsubstituted branched or unbranched C₁₋₆alkyl,C₂₋₆alkenyl or C₂₋₆alkynyl, and in particular CH₃, CF₃, vinyl bromide,—CR²R²—S(O)_(n)—R³, —CR²R²NH₂, —CR²R²NHR², —CR²R²NR², R³ and—CR²R²—C(═O)R²); —CN, or halo (F, Cl, Br or I);

[0036] (d) Y is O, S or S(O)_(n);

[0037] (e) each W is independently O, S, —NH₂, —NHR², —NR²R², —N—CN,—N—NH₂, —N—NHR², —N—NR²R³, —N—OH or —N—OR²;

[0038] (f) each R² is independently hydrogen or an optionallysubstituted or unsubstituted branched or unbranched lower alkyl, alkenylor alkynyl (such as an optionally substituted or unsubstituted branchedor unbranched C₁₋₃alkyl, C₂₋₄alkenyl or C₂₋₄alkynyl, and in particularCH₃, CF₃, vinyl bromide, —CR²R²—S(O)_(n)—R³, —CR²R²NH₂, —CR²R²NHR²,—CR²R²NR²R³ and —CR²R²—C(═O)R²);

[0039] (g) each R³ is independently hydrogen; optionally substituted orunsubstituted branched or unbranched alkyl, alkenyl or alkynyl (such asan optionally substituted or unsubstituted branched or unbranchedC₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, and in particular CH₃, CF₃, vinylbromide, —CR²R²—S(O)_(n)—R³, —CR²R²NH₂, —CR²R²NHR², —CR²R²NR²R³ and—CR²R²—C(═O)R²); optionally substituted or unsubstituted aryl (such asphenyl); optionally substituted or unsubstituted heterocycle; optionallysubstituted or unsubstituted alkylaryl, optionally substituted orunsubstituted alkylhereterocycle, optionally substituted orunsubstituted aralkyl, optionally substituted or unsubstitutedheterocycle-alkyl;

[0040] (h) each n is independently 0, 1 or 2; and

[0041] (i) each p is independently 0, 1, 2, 3, 4 or 5;

[0042] (j) wherein if one or more of the optionally substituted branchedor unbranched alkyl, alkenyl, alkynyl, lower alkyl, lower alkenyl orlower alkynyl; acyl; aryl; heterocycle; alkaryl; alkheterocycle;arylalkyl or alkylheterocycle substitutents is substituted, thenpreferably it is substituted with one or more of halogen (F, Cl, Br orI), —OH, —OR², —SH, —SR², oxime (defined herein as —CH═N—OH), hydrazine(defined herein as —NH—NH₂), —C(═O)H, —C(═W)H, —C(═O)R², —C(═W)R²,—C(═O)OH, —C(═W)OH, —C(═O)OR², —C(═W)OR², —C(═O)SH, —C(═W)SH, —C(═O)SR²,—C(═W)SR², —C(═O)NH₂, —C(═W)NH₂, —C(═O)—NHR², —C(═W)NHR², —C(═O)NR²R³,—C(═W)—NR²R³, —NH₂, —NHR², —NR²R³, —NHSO₂—C₁₋₃alkyl, —NW²SO₂—C₁₋₃alkyl,—NHCO—C₁₋₃alkyl, —NR²CO—C₁₋₃alkyl, —S(O)_(n)—R³, C₁₋₃alkoxy,C₁₋₃thioether, a residue of an amino acid such as —NH(CH₂)_(p)-(aminoacid) or —C(═W)NH(CH₂)_(p)-(amino acid).

[0043] In a preferred embodiment, Y is SO₂. In another preferredembodiment, Z is an amide function.

[0044] In an alternative embodiment, the hydrogen attached to the indolenitrogen can be replaced with lower alkyl, for example, methyl, or aryl,alkaryl or aralkyl.

[0045] In another embodiment the invention provides a phenylindolerepresented generally by formula (I) above, and methods of using suchphenylindoles in the treatment of HIV, wherein:

[0046] (a) R¹ is hydrogen;

[0047] (b) R^(4′), R^(5′), R^(6′) and R^(7′) are independently hydrogen,halogen (F, Cl, Br or I), —NO₂, —CN, —OR², —NR²R², —NHSO₂—C₁₋₃alkyl,—NHCO—C₁₋₃alkyl, oxime, hydrazine, or C₁₋₃ alkyl or alkenyl optionallysubstituted with one or more of —OH, —SH, —C(O)H, —COOH, halogen (F, Cl,Br or I), —NR²R², —C₁₋₃ alkoxy or —C₁₋₃ thioether; wherein if R^(5′) ishydrogen, F, Cl, Br, —NO₂, —CN, —OR², —NR²R², —NHSO₂—C₁₋₃alkyl or—NHCO—C₁₋₃alkyl, then at least one of R^(4′), R^(6′) and R^(7′) is nothydrogen;

[0048] (c) R^(2″), R^(3″), R^(4″), R^(5″) and R^(6″) are independentlyhydrogen, halogen (F, Cl, Br or I), —NO₂, —CN, —OH, —OR², —NR²R²,—NHSO₂—C₁₋₃allkyl, —NHCO—C₁₋₃alkyl, —C₁₋₅ alkoxy, oxime, hydrazine,—C₁₋₅ alkyl or alkenyl optionally substituted with one or more of —OH,—SH, —C(O)H, —COOH, halogen (F, Cl, Br or I), —NR²R², —C₁₋₅ thioether or—C₁₋₅ alkoxy;

[0049] (d) Z is —CN, —C(═W)NR²R³, —C(═O)R³, —C(═O)OR³,—CR²R²—S(O)_(n)—R³, —CR²R²NHR², —CR²R²—CO—R³ or substituted orunsubstituted lower alkyl;

[0050] (e) Y is O, S, or S(O)_(n);

[0051] (f) each W is independently O, S, —N—CN or —N—OR²;

[0052] (g) R² is hydrogen or C₁₋₃ alkyl;

[0053] (h) R³ is hydrogen, substituted or unsubstituted alkyl, alkenyl,aryl, or heterocycle, —C₁₋₅ alkoxy, —OH, —NR²R², or —(CH₂)_(p)C(O)NR²R²,

[0054] (i) each n is independently 0, 1 or 2; and

[0055] (j) each p is independently 0, 1, 2, 3, 4, or 5.

[0056] In still another embodiment the invention provides a phenylindolerepresented generally by formula (I) above, and methods of using suchphenylindoles in the treatment of HIV, wherein:

[0057] (a) R¹ is hydrogen;

[0058] (b) R^(4′), R^(5′), R^(6′), R^(7′), are independently hydrogen,halogen (F, Cl, Br or I), —NO₂, —CN, —OR², —NR²R², —NHSO₂—C₁₋₃alkyl,—NHCO—C₁₋₃alkyl, oxime (defined herein as —CH═N—OH), hydrazine (definedherein as —NH—NH₂), or C₁₋₃ alkyl or alkenyl optionally substituted withone or more of —OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, orC₁₋₃ thioether; wherein if R^(5′) is hydrogen, F, Cl, Br, —NO₂, —CN,—OR², —NR²R², —NHSO₂—C₁₋₃alkyl or —NHCO—C₁₋₃alkyl, then at least one ofR^(4′), R^(6′) and R^(7′) is not hydrogen;

[0059] (c) R^(2″), R^(3″), R^(4″), R^(5″), and R⁶″, are independentlyhydrogen, halogen (F, Cl, Br or I), —NO₂, —CN, —OR², —NHSO₂—C₁₋₃alkyl,—NHCO—C₁₋₃alkyl, oxime, hydrazine, —C₁₋₅ alkyl or alkenyl optionallysubstituted with one or more of —OH, —SH, C(O)H, COOH, halogen, NR²R²,C₁₋₅ thioether, or C₁₋₅ alkoxy, —C₁₋₅ alkoxy, —OH, or —NR²R²,

[0060] (d) Z is —C(W)NR²R³, or —COR³,

[0061] (e) Y is —S(O)_(n)— or —O—, in which n is 0, 1 or 2.

[0062] (f) W is O, S, —N—CN or —N—OR²;

[0063] (g) R² is hydrogen or C₁₋₃ alkyl,

[0064] (h) R³ is s alkyl, C₁₋₅ alkenyl, aryl, or heterocycle,substituted with one or more of C(O)NR²R², —NR²R², —(CH₂)_(m)C(O)NR¹R²,—(CH₂)_(m)C(═W)—NH(CH₂)_(p)-(amino acid);

[0065] (k) each n is independently 0, 1 or 2; and

[0066] (l) each p is independently 0, 1, 2, 3, 4, or 5.

[0067] In a particular embodiment, the phenylindole is a compound of thestructure:

[0068] or a pharmaceutically acceptable salt or prodrug thereof.

[0069] In another particular embodiment, the phenylindole is a compoundof the structure:

[0070] or a pharmaceutically acceptable salt or prodrug thereof.

[0071] In yet another particular embodiment, the phenylindole is acompound of the structure:

[0072] or a pharmaceutically acceptable salt or prodrug thereof.

[0073] In yet another particular embodiment, the phenylindole is acompound of the structure:

[0074] or a pharmaceutically acceptable salt or prodrug thereof.

[0075] In another particular embodiment, the phenylindole is a compoundof the structure:

[0076] or a pharmaceutically acceptable salt or prodrug thereof.

[0077] In yet another particular embodiment of the present invention,the phenylindole is a compound of the structure:

[0078] or a pharmaceutically acceptable salt or prodrug thereof.

[0079] In yet another particular embodiment of the present invention,the phenylindole is a compound of the structure:

[0080] or a pharmaceutically acceptable salt or prodrug thereof.

[0081] In yet another particular embodiment of the present invention,the phenylindole is a compound of the structure:

[0082] or a pharmaceutically acceptable salt or prodrug thereof.

[0083] The phenylindoles of this invention belong to a class of anti-HIVagents that may inhibit reverse transcriptase activity. These compoundscan be assessed for their ability to inhibit reverse transcriptaseactivity _(in vitro) according to standard screening methods.

[0084] In one embodiment the efficacy of the anti-HIV compound ismeasured according to the concentration of compound necessary to reducethe plaque number of the virus in vitro, according to methods set forthmore particularly herein, by 50% (i.e. the compound's EC₅₀). Inpreferred embodiments the compound exhibits an EC₅₀ of less than 15 orpreferably, less than 10 micromolar in vitro.

[0085] In another embodiment, the active compound exhibits significantactivity against drug-resistant forms of HIV, and thus exhibitsdecreased cross-resistance against currently approved antiviraltherapies. The term significant activity against a drug resistant formof HIV means that a compound (or its prodrug or pharmaceuticallyacceptable salt) is active against the mutant strain with an EC₅₀against the mutant strain of less than approximately 50, 25, 10 or 1micromolar concentration. In a preferred embodiment, the non-nucleosidesreverse transcriptase inhibitors (NNRTI) displays an EC₅₀ (in molarconcentrations) in a mutant HIV strain of less than approximately 5,2.5, 1 or 0.1 micromolar concentration. In one non limiting embodiment,the HIV mutant strain is a strain with a reverse transcriptase mutationat lysine 103_(→) asparagine and/or tyrosine 181_(→) cysteine.

[0086] In still another embodiment, the active compound can beadministered in combination or alternation with another anti-HIV agent.In combination therapy, effective dosages of two or more agents areadministered together, whereas during alternation therapy an effectivedosage of each agent is administered serially. The dosages will dependon absorption, inactivation, and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens and schedules should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions.

BRIEF DESCRIPTION OF THE FIGURES

[0087]FIG. 1 is a nonlimiting illustrative example of the synthesis ofphenylindoles as described herein; wherein P represents hydrogen oralkyl, in particular methyl, ethyl, butyl or propyl, preferably ethyl;and Y′ represents oxygen or sulfur.

[0088]FIG. 2 is a nonlimiting illustrative example of the synthesis ofphenylindoles as described herein; wherein P represents hydrogen oralkyl, in particular methyl, ethyl, butyl or propyl, preferably ethyl.

[0089]FIGS. 3 and 4 are additional nonlimiting illustrative example ofthe synthesis of phenylindoles as described herein.

[0090]FIG. 5 is a schematic of a method of manufacture of the compoundof the formula:

DETAILED DESCRIPTION OF THE INVENTION

[0091] The invention as disclosed herein is a method and composition forthe treatment of HIV in humans and other host animals, that includes theadministration of an effective HIV treatment amount of a phenylindole asdescribed herein or a pharmaceutically acceptable salt or prodrugthereof, optionally in a pharmaceutically acceptable carrier.

[0092] The compounds of this invention either possess antiviral (i.e.,anti-HIV) activity, or are metabolized to a compound that exhibits suchactivity.

[0093] In summary, the present invention includes the followingfeatures:

[0094] phenylindoles and their pharmaceutically acceptable salts andprodrugs thereof as described herein;

[0095] phenylindoles and their pharmaceutically acceptable salts andprodrugs thereof as described herein substantially free of otherchemical entities;

[0096] phenylindoles and their pharmaceutically acceptable salts andprodrugs thereof as described herein that are effective against HIV in ahost;

[0097] phenylindoles and their pharmaceutically acceptable salts andprodrugs thereof as described herein that are effective againstdrug-resistant strains of HIV in a host;

[0098] phenylindoles and their pharmaceutically acceptable salts andprodrugs thereof as described herein that are effective againstdrug-resistant strains of HIV due to a reverse transcriptase mutation,such as lysine 103→asparagine and/or tyrosine 181→cysteine;

[0099] phenylindoles and their pharmaceutically acceptable salts andprodrugs thereof as described herein for use in the treatment orprophylaxis of an HIV infection in a host, especially in individualsdiagnosed as having an HIV infection or being at risk for becominginfected by HIV;

[0100] phenylindoles and their pharmaceutically acceptable salts andprodrugs thereof as described herein for use in the manufacture of amedicament for the treatment or prophylaxis of an HIV infection in ahost, especially in individuals diagnosed as having an HIV infection orbeing at risk for becoming infected by HIV;

[0101] phenylindoles and their pharmaceutically acceptable salts andprodrugs thereof as described herein for use in the treatment orprophylaxis of an HIV infection, which is resistant to one or morereverse transcriptase inhibitors, in a host;

[0102] phenylindoles and their pharmaceutically acceptable salts andprodrugs thereof as described herein for use in the manufacture of amedicament for the treatment or prophylaxis of an HIV infection, whichis resistant to one or more reverse transcriptase inhibitors, in a host;

[0103] phenylindoles and their pharmaceutically acceptable salts andprodrugs thereof as described herein for use in the treatment orprophylaxis of an HIV infection as a form of salvage therapy in a host,especially in individuals diagnosed as having an HIV infection or beingat risk for becoming infected by HIV;

[0104] phenylindoles and their pharmaceutically acceptable salts andprodrugs thereof as described herein for use in the manufacture of amedicament for the treatment or prophylaxis of an HIV infection as aform of salvage therapy in a host, especially in individuals diagnosedas having an HIV infection or being at risk for becoming infected byHIV;

[0105] phenylindoles and their pharmaceutically acceptable salts andprodrugs thereof as described herein for use in the treatment orprophylaxis of an HIV infection that is resistant to one or more reversetranscriptase inhibitors due to a reverse transcriptase mutation, suchas lysine 103→asparagine and/or tyrosine 181→cysteine, in a host,especially in individuals diagnosed as having an HIV infection or beingat risk for becoming infected by HIV;

[0106] phenylindoles and their pharmaceutically acceptable salts andprodrugs thereof as described herein for use in the manufacture of amedicament for the treatment or prophylaxis of an HIV infection that isresistant to one or more reverse transcriptase inhibitors due to areverse transcriptase mutation, such as lysine 103→asparagine and/ortyrosine 181→cysteine, in a host, especially in individuals diagnosed ashaving an HIV infection or being at risk for becoming infected by HIV;

[0107] processes for the preparation of phenylindoles, as described inmore detail below;

[0108] processes for the preparation of phenylindoles substantiallyisolated from other chemical entities;

[0109] pharmaceutical compositions comprising an effective anti-HIVtreatment amount of a phenylindole or its pharmaceutically acceptablesalt or prodrug thereof together with a pharmaceutically acceptablecarrier or diluent;

[0110] pharmaceutical compositions comprising an effective anti-HIVtreatment amount of a phenylindole or its pharmaceutically acceptablesalt or prodrug thereof in combination with one or more other anti-HIVagent, optionally with a pharmaceutically acceptable carrier or diluent;

[0111] pharmaceutical compositions for the treatment or prophylaxis ofan HIV infection in a host comprising an effective anti-HIV treatmentamount of a phenylindole or its pharmaceutically acceptable salt orprodrug thereof, optionally in combination with one or more otheranti-HIV agent, optionally with a pharmaceutically acceptable carrier ordiluent;

[0112] pharmaceutical compositions for the treatment or prophylaxis ofan HIV infection, which is resistant to one or more reversetranscriptase inhibitors, in a host comprising an effective anti-HIVtreatment amount of a phenylindole or its pharmaceutically acceptablesalt or prodrug thereof, optionally in combination with one or moreother anti-HIV agent, optionally with a pharmaceutically acceptablecarrier or diluent;

[0113] pharmaceutical compositions for the treatment or prophylaxis ofan HIV infection in a host as a form of salvage therapy comprising aneffective anti-HIV treatment amount of a phenylindole or itspharmaceutically acceptable salt or prodrug thereof, optionally incombination with one or more other anti-HIV agent, optionally with apharmaceutically acceptable carrier or diluent;

[0114] pharmaceutical compositions for the treatment or prophylaxis ofan HIV infection, which is resistant to one or more reversetranscriptase inhibitors due to a reverse transcriptase mutation, suchas lysine 103→asparagine and/or tyrosine 181→cysteine, in a hostcomprising an effective anti-HIV treatment amount of a phenylindole orits pharmaceutically acceptable salt or prodrug thereof, optionally incombination with one or more other anti-HIV agent, optionally with apharmaceutically acceptable carrier or diluent;

[0115] methods for the treatment or prophylaxis of an HIV infection in ahost comprising administering to said host an effective anti-HIVtreatment amount of a phenylindole or its pharmaceutically acceptablesalt or prodrug thereof, optionally in combination and/or alternationwith one or more other anti-HIV agent, optionally with apharmaceutically acceptable carrier or diluent;

[0116] methods for the treatment or prophylaxis of an HIV infection,which is resistant to one or more reverse transcriptase inhibitors, in ahost comprising administering to said host an effective anti-HIVtreatment amount of a phenylindole or its pharmaceutically acceptablesalt or prodrug thereof, optionally in combination and/or alternationwith one or more other anti-HIV agent, optionally with apharmaceutically acceptable carrier or diluent;

[0117] methods for the treatment or prophylaxis of an HIV infection in ahost as a form of salvage therapy comprising administering to said hostan effective anti-HIV treatment amount of a phenylindole or itspharmaceutically acceptable salt or prodrug thereof, optionally incombination and/or alternation with one or more other anti-HIV agent,optionally with a pharmaceutically acceptable carrier or diluent;

[0118] methods for the treatment or prophylaxis of an HIV infection,which is resistant to one or more reverse transcriptase inhibitors dueto a reverse transcriptase mutation, such as lysine 103→asparagineand/or tyrosine 181→cysteine, in a host comprising administering to saidhost an effective anti-HIV treatment amount of a phenylindole or itspharmaceutically acceptable salt or prodrug thereof, optionally incombination and/or alternation with one or more other anti-HIV agent,optionally with a pharmaceutically acceptable carrier or diluent;

[0119] use of a phenylindole or its pharmaceutically acceptable salt orprodrug thereof, optionally in combination and/or alternation with oneor more other anti-HIV agent, optionally with a pharmaceuticallyacceptable carrier or diluent for the treatment or prophylaxis of an HIVinfection in a host;

[0120] use of a phenylindole or its pharmaceutically acceptable salt orprodrug thereof, optionally in combination and/or alternation with oneor more other anti-HIV agent, optionally with a pharmaceuticallyacceptable carrier or diluent for the treatment or prophylaxis of an HIVinfection, which is resistant to one or more reverse transcriptaseinhibitors, in a host;

[0121] use of a phenylindole or its pharmaceutically acceptable salt orprodrug thereof, optionally in combination and/or alternation with oneor more other anti-HIV agent, optionally with a pharmaceuticallyacceptable carrier or diluent for the treatment or prophylaxis of an HIVinfection in a host as a form of salvage therapy;

[0122] use of a phenylindole or its pharmaceutically acceptable salt orprodrug thereof, optionally in combination and/or alternation with oneor more other anti-HIV agent, optionally with a pharmaceuticallyacceptable carrier or diluent for the treatment or prophylaxis of an HIVinfection, which is resistant to one or more reverse transcriptaseinhibitors due to a reverse transcriptase mutation, such as lysine103→asparagine and/or tyrosine 181→cysteine, in a host;

[0123] use of a phenylindole or its pharmaceutically acceptable salt orprodrug thereof, optionally in combination and/or alternation with oneor more other anti-HIV agent, optionally with a pharmaceuticallyacceptable carrier or diluent in the manufacture of a medicament for thetreatment or prophylaxis of an HIV infection in a host;

[0124] use of a phenylindole or its pharmaceutically acceptable salt orprodrug thereof, optionally in combination and/or alternation with oneor more other anti-HIV agent, optionally with a pharmaceuticallyacceptable carrier or diluent in the manufacture of a medicament for thetreatment or prophylaxis of an HIV infection, which is resistant to oneor more reverse transcriptase inhibitors, in a host;

[0125] use of a phenylindole or its pharmaceutically acceptable salt orprodrug thereof, optionally in combination and/or alternation with oneor more other anti-HIV agent, optionally with a pharmaceuticallyacceptable carrier or diluent in the manufacture of a medicament for thetreatment or prophylaxis of an HIV infection in a host as a form ofsalvage therapy; and

[0126] use of a phenylindole or its pharmaceutically acceptable salt orprodrug thereof, optionally in combination and/or alternation with oneor more other anti-HIV agent, optionally with a pharmaceuticallyacceptable carrier or diluent in the manufacture of a medicament for thetreatment or prophylaxis of an HIV infection, which is resistant to oneor more reverse transcriptase inhibitors due to a reverse transcriptasemutation, such as lysine 103→asparagine and/or tyrosine 181→cysteine, ina host.

[0127] I. Active Compounds of the Present Invention

[0128] Suitable phenylindoles for practicing the present invention canbe represented generally by formula (I):

[0129] or its pharmaceutically acceptable salt or prodrug thereof, andare defined below.

[0130] In one embodiment of the present invention the compound offormula (I) is defined as follows:

[0131] (a) R¹ is hydrogen; acyl; —C(═O)H; —C(═W)H; —C(═O)R²; —C(═W)R²;—C(═O)OH; —C(═W)OH; —C(═O)OR²; —C(═W)OR²; —C(═O)SH; —C(═W)SH; —C(═O)SR²;—C(═W)SR²; —C(═O)NH₂; —C(═W)NH₂; —C(═O)NHR²; —C(═W)NHR²; —C(═O)NR²R³;—C(═W)NR²R³; —C(═W)NH—(CH₂)_(p)-(amino acid) or —(CH₂)_(p)-(amino acid);

[0132] (b) R^(4′), R^(5′), R^(6′), R^(7′), R^(2″), R^(3″), R^(4″),R^(5″) and R^(6″) are each independently H; halo (F, Cl, Br or I); —NO₂;—CN; —OH; —OR²; —SH; —SR²; —NH₂; —NHR²; —NR²R³; —NHSO₂—C₁₋₃alkyl;—NR²SO₂—C₁₋₃alkyl; —NHCO—C₁₋₃alkyl; —NR²CO—C₁₋₃alkyl; optionallysubstituted or unsubstituted branched or unbranched alkyl, alkenyl oralkynyl (such as an optionally substituted or unsubstituted branched orunbranched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, and in particular CH₃,CF₃, vinyl bromide, —CR²R²—S(O)_(n)—R³, —CR²R²NH₂, —CR²R²NHR²,—CR²R²NR²R³ and —CR²R²—C(═O)R²); alkacyl; optionally substituted orunsubstituted acyl; —C(═O)H; —C(═W)H; —C(═O)R²; —C(═W)R²; —C(═O)OH;—C(═W)OH; —C(═O)OR²; —C(═W)OR²; —C(═O)—SH; —C(═W)SH; —C(═O)SR²;—C(═W)SR²; —C(═O)NH₂; —C(═W)NH₂; —C(═O)NHR²; —C(═W)NHR²; —C(═O)NR²R³;—C(═W)—NR²R³, —C(═W)NH(CH₂)_(p)-(amino acid), a residue of an amino acidor —(CH₂)_(p)(amino acid); wherein if R^(5′) is hydrogen, F, Cl, Br,—NO₂, —CN, —OR², —NR²R², —NHSO₂—C₁₋₃alkyl or —NHCO—C₁₋₃alkyl, then atleast one of R^(4′), R^(6′) and R^(7′) is not hydrogen;

[0133] (c) Z is optionally substituted or unsubstituted acyl, —C(═O)NH₂;—C(═W)—NH₂; —C(═O)NHR²; —C(═W)NHR²; —C(═O)NR²R³; —C(═W)NR²R³;—C(═W)NH(CH₂)_(p)-(amino acid); a residue of an amino acid,—(CH₂)_(p)-(amino acid); —C(═O)R³; —C(═O)H; —C(═W)H; —C(═O)R²; —C(═W)R²;—C(═O)OR³; —C(═O)OH; —C(═W)OH; —C(═O)OR²; —C(═W)—OR²; —C(═O)—SH;—C(═W)SH; —C(═O)SR²; —C(═W)SR²; optionally substituted or unsubstitutedbranched or unbranched alkyl, alkenyl or alkynyl (such as an optionallysubstituted or unsubstituted branched or unbranched C₁₋₆alkyl,C₂₋₆alkenyl or C₂₋₆alkynyl, and in particular CH₃, CF₃, vinyl bromide,—CR²R²—S(O)_(n)—R³, —CR²R²NH₂, —CR²R²NHR², —CR²R²NR²R³ and—CR²R²—C(═O)R²); —CN, or halo (F, Cl, Br or I);

[0134] (d) Y is O, S or S(O)_(n);

[0135] (e) each W is independently O, S, —NH₂, —NHR², —NR²R², —N—CN,—N—NH₂, —N—NHR², —N—NR²R³, —N—OH or —N—OR²;

[0136] (f) each R² is independently hydrogen or an optionallysubstituted or unsubstituted branched or unbranched lower alkyl, alkenylor alkynyl (such as an optionally substituted or unsubstituted branchedor unbranched C₁₋₃alkyl, C₂₋₄alkenyl or C₂₋₄alkynyl, and in particularCH₃, CF₃, vinyl bromide, —CR²R²—S(O)_(n)—R³, —CR²R²NH₂, —CR²R²NHR²,—CR²R²NR²R³ and —CR²R²—C(═O)R²);

[0137] (g) each R³ is independently hydrogen; optionally substituted orunsubstituted branched or unbranched alkyl, alkenyl or alkynyl (such asan optionally substituted or unsubstituted branched or unbranchedC₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, and in particular CH₃, CF₃, vinylbromide, —CR²R²—S(O)_(n)—R³, —CR²R²NH₂, —CR²R²NHR², —CR²R²NR²R³ and—CR²R²—C(═O)R²); optionally substituted or unsubstituted aryl (such asphenyl); optionally substituted or unsubstituted heterocycle; optionallysubstituted or unsubstituted alkylaryl, optionally substituted orunsubstituted alkylhereterocycle, optionally substituted orunsubstituted aralkyl, optionally substituted or unsubstitutedheterocycle-alkyl;

[0138] (h) each n is independently 0, 1 or 2; and

[0139] (i) each p is independently 0, 1, 2, 3, 4 or 5;

[0140] (j) wherein if one or more of the optionally substituted branchedor unbranched alkyl, alkenyl, alkynyl, lower alkyl, lower alkenyl orlower alkynyl; acyl; aryl; heterocycle; alkaryl; alkheterocycle;arylalkyl or alkylheterocycle substitutents is substituted, thenpreferably it is substituted with one or more of halogen (F, Cl, Br orI), —OH, —OR², —SH, —SR², oxime, hydrazine, —C(═O)H, —C(═W)H, —C(═O)R²,—C(═W)R², —C(═O)OH, —C(═W)OH, —C(═O)OR², —C(═W)OR², —C(═O)SH, —C(═W)SH,—C(═O)SR², —C(═W)SR², —C(═O)NH₂, —C(═W)NH₂, —C(═O)—NHR², —C(═W)NHR²,—C(═O)NR²R³, —C(═W)—NR²R³, —NH₂, —NHR², —NR²R³, —NHSO₂—C₁₋₃alkyl,—NR²SO₂—C₁₋₃alkyl, —NHCO—C₁₋₃alkyl, —NR²CO—C₁₋₃alkyl, —S(O)_(n)—R³, C₁₋₃alkoxy, C₁₋₃thioether, a residue of an amino acid such as—NH(CH₂)_(p)-(amino acid) or —C(═W)NH(CH₂)_(p)-(amino acid.

[0141] In a preferred embodiment, Y is SO₂. In another preferredembodiment, Z is an amide function.

[0142] In an alternative embodiment, the hydrogen attached to the indolenitrogen can be replaced with lower alkyl, for example, methyl, or aryl,alkaryl or aralkyl.

[0143] In another embodiment the invention provides a phenylindolerepresented generally by formula (I) above, wherein:

[0144] (a) R¹ is hydrogen;

[0145] (b) R^(4′), R^(5′), R^(6′) and R^(7′) are independently hydrogen,halogen (F, Cl, Br or I), —NO₂, —CN, —OR², —NR²R², —NHSO₂—C₁₋₃alkyl,—NHCO—C₁₋₃alkyl, oxime, hydrazine, or C₁₋₃ alkyl or alkenyl optionallysubstituted with one or more of —OH, —SH, —C(O)H, —COOH, halogen (F, Cl,Br or I), —NR²R², —C₁₋₃ alkoxy or —C₁₋₃ thioether; wherein if R^(5′) ishydrogen, F, Cl, Br, —NO₂, —CN, —OR², —NR²R², —NHSO₂—C₁₋₃alkyl or—NHCO—C₁₋₃alkyl, then at least one of R^(4′), R^(6′) and R^(7′) is nothydrogen;

[0146] (c) R^(2″), R^(3″), R^(4″), R^(5″) and R⁶″ are independentlyhydrogen, halogen (F, Cl, Br or I), —NO₂, —CN, —OH, —OR², —NR²R²,—NHSO₂—C₁₋₃alkyl, —NHCO—C₁₋₃alkyl, —C₁₋₅ alkoxy, oxime, hydrazine, —C₁₋₅alkyl or alkenyl optionally substituted with one or more of —OH, —SH,—C(O)H, —COOH, halogen (F, Cl, Br or I), —NR²R², —C₁₋₅ thioether or—C₁₋₅ alkoxy;

[0147] (d) Z is —CN, —C(═W)NR²R³, —C(═O)R³, —C(═O)OR³,—CR²R²—S(O)_(n)—R³, —CR²R²NHR², —CR²R²—CO—R³ or substituted orunsubstituted lower alkyl;

[0148] (e) Y is O, S, or S(O)_(n);

[0149] (f) each W is independently O, S, —N—CN or —N—OR²;

[0150] (g) R² is hydrogen or C₁₋₃ alkyl;

[0151] (h) R³ is hydrogen, substituted or unsubstituted alkyl, alkenyl,aryl, or heterocycle, —C₁₋₅ alkoxy, —OH, —NR²R², or —(CH₂)_(p)C(O)NR²R²,

[0152] (i) each n is independently 0, 1 or 2; and

[0153] (j) each p is independently 0, 1, 2, 3, 4, or 5.

[0154] In still another embodiment the invention provides a phenylindolerepresented generally by formula (I) above, wherein:

[0155] (a) R¹ is hydrogen;

[0156] (b) R^(4′), R^(5′), R^(6′), R^(7′), are independently hydrogen,halogen (F, Cl, Br or I), —NO₂, —CN, —OR², —NR²R², —NHSO₂—C₁₋₃alkyl,—NHCO—C₁₋₃alkyl, oxime, hydrazine, or C₁₋₃ alkyl or alkenyl optionallysubstituted with one or more of —OH, —SH, C(O)H, COOH, halogen, NR²R²,C₁₋₃ alkoxy, or C₁₋₃ thioether; wherein if R^(5′) is hydrogen, F, Cl,Br, —NO₂, —CN, —OR², —NR²R², —NHSO₂—C₁₋₃alkyl or —NHCO—C₁₋₃alkyl, thenat least one of R^(4′), R^(6′) and R^(7′) is not hydrogen;

[0157] (c) R^(2″), R^(3″), R^(4″), R^(5″), and R^(6″), are independentlyhydrogen, halogen (F, Cl, Br or I), —NO₂, —CN, —OR², —NHSO₂—C₁₋₃alkyl,—NHCO—C₁₋₃alkyl, oxime, hydrazine, —C₁₋₅ alkyl or alkenyl optionallysubstituted with one or more of —OH, —SH, C(O)H, COOH, halogen, NR²R²,Cl ₅ thioether, or C₁₋₅ alkoxy, —C₁₋₅ alkoxy, —OH, or —NR²R²,

[0158] (d) Z is —C(W)NR²R³, or —COR³,

[0159] (e) Y is —S(O)_(n)— or —O—, in which n is 0, 1 or 2.

[0160] (f) W is O, S, —N—CN or —N—OR²;

[0161] (g) R² is hydrogen or C₁₋₃ alkyl,

[0162] (h) R³ is C₁₋₅ alkyl, C₁₋₅ alkenyl, aryl, or heterocycle,substituted with one or more of C(O)NR²R², —NR²R², —(CH₂)_(m)C(O)NR2R²,—(CH₂)_(m)C(═W) NH(CH₂)_(p)-(amino acid);

[0163] (k) each n is independently 0, 1 or 2; and

[0164] (l) each p is independently 0, 1, 2, 3, 4, or 5.

[0165] In the first principal embodiment, the variables are defined asfollows:

[0166] (a) Z is (i) —C(W)NR²R³, or (ii) —COR³,

[0167] (b) R² is hydrogen, or C₁₋₅ alkyl optionally substituted with—OH, or NR²R²,

[0168] (c) R³ is (i) —NR²R², or (ii) —(CH₂)_(m)C(O)NR²R², (iii) C₁₋₅alkyl, C₁₋₅ alkenyl, aryl, or heterocycle, substituted with one or moreof C(O)NR²R², or (iv) a residue of an amino acid or —NH(CH₂)_(p)-(aminoacid),

[0169] (d) W is O, S, —N—CN, or —N—OR²,

[0170] (e) m is 1,2,3,4, or 5,

[0171] (f) R^(4′), R^(5′), R^(6′), R^(7′), are independently (i) H,(ii), halo, (iii) —NO₂, (iv) —CN, (v) —OR², (vi) —NR²R², (vii)—NHSO₂—C₁₋₃alkyl, (viii) —NHCO—C₁₋₃alkyl, (ix) oxime, (x) hydrazine, or(xi) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether,

[0172] (g) R^(2″), R^(3″), R^(4″), R^(1″), and R^(6″), are independently(i) hydrogen, (ii) halogen, (iii) NO₂, (iv) —CN, (v) —OR², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,(x) —C₁₋₅ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₅ thioether, or C₁₋₅ alkoxy,(xi) —C₁₋₅ alkoxy, (xii) —OH, or (ix) —NR²R², and

[0173] (h) Y is —S(O)_(n)— or —O—, in which n is 0, 1, or 2.

[0174] A first series of preferred subembodiments of the first principalembodiment are defined when Z is defined as follows:

[0175] 1) Z is C(O)NR²R³, R² is hydrogen, and R³ is NR²R²

[0176] 2) Z is C(O)NR²R³, R² is hydrogen, and R³ is NR²R², and R² isC₁₋₅ alkyl optionally substituted with OH

[0177] 3) Z is C(O)NR²R³, R² is hydrogen, and R³ is (CH₂)_(m)C(O)NR²R²

[0178] 4) Z is C(O)NR²R³, R² is hydrogen, and R³ is alkyl substituted bysubstituted or unsubstituted aryl or heterocycle

[0179] 5) Z is C(O)R³, R³ is a residue of an amino acid or—NH(CH₂)_(p)-(amino acid)

[0180] 6) Z is —C(O)NHNHC₂H₅OH,

[0181] 7) Z is —C(O)NHCH₂C(O)NH₂

[0182] 8) Z is —C(O)NHCH₂CONHNH₂

[0183] 9) Z is —C(O)NHCH₂CH₂-(2NO₂,5Me imidazole)

[0184] 10) Z is —C(O)NHCH₂NHCH(CH₃)COOH

[0185] 11) Z is —C(O)CH═CHC(O)NH₂

[0186] A second series of preferred subembodiments of the firstprincipal embodiment are defined when R^(4′), R^(5′), R^(6′), and R^(7′)are defined as follows:

[0187] 1) R^(4′), R^(6′), and R^(7′) are hydrogen, and R^(5′) is (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,or (x) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether,

[0188] 2) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,or (x) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether,

[0189] 3) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,or (x) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether,

[0190] 4) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,or (x) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether,

[0191] 5) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², or (vi) C₁₋₃ alkyl oralkenyl optionally substituted with one or more of —OH, —SH, C(O)H,COOH, halogen, or NH₂,

[0192] 6) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², or (vi) C₁₋₃ alkyl oralkenyl optionally substituted with one or more of —OH, —SH, C(O)H,COOH, halogen, or NH₂,

[0193] 7) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², or (vi) C₁₋₃ alkyl oralkenyl optionally substituted with one or more of —OH, —SH, C(O)H,COOH, halogen, or NH₂,

[0194] 8) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are haloor C₁₋₃ alkyl or alkenyl substituted with one or more halo,

[0195] 9) R^(4′) and R^(7′) are hydrogen, and R⁵′ and R^(6′) are halo orC₁₋₃ alkyl or alkenyl substituted with one or more halo,

[0196] 10) R^(4′) and R⁶′ are hydrogen, and R^(5′) and R^(7′) are haloor C₁₋₃ alkyl or alkenyl substituted with one or more halo,

[0197] 11) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are Cl,F, CF₃, or vinyl bromide

[0198] 12) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are Cl,F, CF₃, or vinyl bromide

[0199] 13) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are Cl,F, CF₃, or vinyl bromide

[0200] 14) R^(4′), R^(6′) and R^(7′) are hydrogen, and R^(5′) is (i)oxime, (ii) hydrazine, or (iii) C₁₋₃ alkyl or alkenyl optionallysubstituted with one or more of —OH, —SH, C(O)H, COOH, halogen, NR²R²,C₁₋₃ alkoxy, or C₁₋₃ thioether

[0201] 15) R^(4′), R^(6′), and R^(7′) are hydrogen, and R^(5′) is Cl

[0202] 16) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are Cl

[0203] 17) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R⁷′ are F

[0204] 18) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R⁵′ are F

[0205] 19) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are F

[0206] 20) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are F

[0207] 21) R^(4′) and R^(7′) are hydrogen, and R^(5′) is Cl, and R^(6′)is F

[0208] 22) R^(4′) and R^(7′) are hydrogen, and R^(5′) is Cl, and R^(6′)is CF₃

[0209] 23) R^(4′), R^(6′), and R^(7′) are hydrogen, and R^(5′) is CF₃

[0210] 24) R^(4′), R^(6′), and R^(7′) are hydrogen, and R^(5′) is vinylbromide

[0211] A third series of preferred subembodiments of the first principalembodiment are defined when R^(2″), R^(3″), R^(4″), R^(5″), and R^(6″),are defined as follows:

[0212] 1) R^(2″), R^(4″), and R^(6″), are hydrogen, and R^(3″) andR^(5″) are independently (i) halogen, (ii) NO₂, (iii) —CN, (iv) —OR²,(v) —NHSO₂—C₁₋₃alkyl, (vi) —NHCO—C₁₋₃alkyl, (vii) oxime, (vii)hydrazine, (viii) —C₁₋₅ alkyl or alkenyl optionally substituted with oneor more of —OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₅ thioether, orC₁₋₅ alkoxy, (ix) —C₁₋₅ alkoxy, (x) —OH, or (xi) —NR²R²

[0213] 2) R^(2″), R^(4″), and R^(6″), are hydrogen, and R^(3″) andR^(5″) are independently (i) halogen, (ii) NO₂, (iii) —CN, (iv) —OR²,(v) —C₁₋₅ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, COOH, halogen, NR²R², C₁₋₅ thioether, or C₁₋₅ alkoxy, (vi)—C₁₋₅ alkoxy, (vii) —OH, or (viii) —NR²R²

[0214] 3) R^(2″), R^(4″), and R^(6″), are hydrogen, and R^(3″) andR^(5″) are independently (i) halogen, (ii) NO₂, (iii) —CN, (iv) —OR²,(v) —C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, COOH, halogen, or NH₂, (vi) —C₁₋₃ alkoxy, (vii) —OH, or (viii)—NR²R²

[0215] 4) R^(2″), R^(4″), and R^(6″), are hydrogen, and R^(3″) andR^(5″) are independently (i) halogen, or (ii) —C₁₋₃ alkyl or alkenyloptionally substituted with one or more halogen

[0216] 5) R^(2″), R^(3″), R^(4″), R^(5″), and R^(6″), are H

[0217] 6) R^(2″), R^(4″), and R^(6″), are H, and R^(3″) and R^(5′) aremethyl

[0218] 7) R^(2″), R^(4″), and R^(6″), are H, and R^(3″) and R^(5″) areCl

[0219] 8) R^(2″), R^(4″), and R^(6″), are H, and R^(3″) and R^(5″) are F

[0220] 9) R^(2″), R^(4″), and R^(6″), are H, and R^(3″) and R^(5″) areCF₃

[0221] A fourth series of preferred subembodiments are defined when Z isas defined in any one of the first series of preferred subembodiments ofthe first principal embodiment, R^(4′), R^(5′), R^(6′), and R^(7′) a reas defined in any one of the second series of preferred subembodimentsof the first principal embodiment, and R^(2″), R^(3″), R^(4″), R^(5″),and R^(6″), are as defined in the first principal embodiment.

[0222] A fifth series of preferred subembodiments are defined when Z isas defined in any one of the first series of preferred subembodiments ofthe first principal embodiment, R^(4′), R^(5′), R^(6′), and R^(7′) areas defined in the first principal embodiment, and R^(2″), R^(3″),R^(4″), R^(5″), and R^(6″), are as defined in any one of the thirdseries of preferred subembodiment of the first principal embodiment.

[0223] A sixth series of preferred subembodiments are defined when Z isas defined in the first principal embodiment, R^(4′), R^(5′), R^(6′),and R^(7′) are as defined in any one of the second series of preferredsubembodiments of the first principal embodiment, and R^(2″), R^(3″),R^(4″), R^(5″), and R^(6″), are as defined in any one of the thirdseries of preferred subembodiments of the first principal embodiment.

[0224] A seventh series of preferred subembodiments are defined when Zis as defined in any one of the first series of preferred subembodimentsof the first principal embodiment, R^(4′), R^(5′), R^(6′), and R^(7′)are as defined in any one of the second series of preferredsubembodiments of the first principal embodiment, and R^(2″), R^(3″),R^(4″), R^(5″), and R^(6″), are as defined in any one of the thirdseries of preferred subembodiments of the first principal embodiment.

[0225] In each of the subembodiments within the first, second, third,fourth, fifth, sixth, and seventh preferred series of subembodiments ofthe first principal embodiment, Y is preferably SO₂.

[0226] Preferred species of the first principal embodiment are definedwhen:

[0227] 1) Z is —C(O)NHNHC₂H₅OH, R^(4′), R^(6′), and R^(7′) are hydrogen,R^(5′) is Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3′) and R^(5″) aremethyl, and Y is SO₂;

[0228] 2) Z is —C(O)NHCH₂C(O)NH₂, R^(4′), R^(6′), and R^(7′) arehydrogen, R^(5′) is Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) andR^(5″) are methyl, and Y is SO₂;

[0229] 3) Z is —C(O)NHCH₂CONHNH₂, R^(4′), R^(6′), and R^(7′) arehydrogen, R^(5′) is Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) andR^(5″) are methyl, and Y is SO₂;

[0230] 4) Z is —C(O)NHCH₂CH₂-(2NO₂,5Me imidazole), R^(4′), R^(6′), andR^(7′) are hydrogen, R^(5′) is Cl, and R^(6″), are H, R^(3″) and R^(5″)are methyl, and Y is SO₂;

[0231] 5) Z is —C(O)NHCH₂NIHCH(CH₃)COOH, R^(4′), R^(6′), and R^(7′) arehydrogen, R^(5′) is Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) andR^(5′) are methyl, and Y is SO₂; and

[0232] 6) Z is —C(O)CH═CHC(O)NH₂, R^(4′), R^(6′), and R^(7′) arehydrogen, R^(5′) is C¹, R^(2″), R^(4″), and R^(6″), are H, R^(3″) andR^(5″) are methyl, and Y is SO₂.

[0233] In a second principal the compound of formula (I) is defined asfollows:

[0234] (a) either (a1) R^(4′), R^(5′), R^(6′), R^(7′), are independently(i) H, (ii), halo, (iii) —NO₂, (iv) —CN, (v) —OR², (vi) —NR²R², (vii)—NHSO₂—C₁₋₃alkyl, (viii) —NHCO—C₁₋₃alkyl, (ix) oxime, (x) hydrazine, or(xi) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether,wherein at least 2 of R^(4′), R^(5′), R^(6′), and R^(7′), are nothydrogen, or (a2) R^(4′), R^(5′), R^(6′), R^(7′), are independently (i)H, (ii), halo, (iii) —NO₂, (iv) —CN, (v) —OR², (vi) —NR²R², (vii)—NHSO₂—C₁—₃alkyl, (viii) —NHCO—C₁₋₃alkyl, (ix) oxime, (x) hydrazine, or(xi) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether,wherein at least one of R^(4′), R^(5′), R^(6′), and R^(7′), is nothydrogen, halogen, —NHSO₂—C₁₋₃alkyl, or OR²,

[0235] (b) Z is (i) C(W)NR²R³, (ii) —COR³, (iii) —COOR³, (iv)—CR²R²—S(O)_(n)—R³, (v) —CR²R²NHR², (vi) —CR²R²—CO—R³, (vii) substitutedor unsubstituted lower alkyl, or (viii) —CN;

[0236] (c) R² is hydrogen, or C₁₋₅ alkyl optionally substituted with—OH, or NR²R²,

[0237] (d) R³ is (i) substituted or unsubstituted alkyl, alkenyl, aryl,or heterocycle, (ii) —C₁₋₅ alkoxy, (iii) —OH, (iv) hydrogen, (v) —NR²R²,(vi) —(CH₂)_(m)C(O)—NR²R², or (vii) a residue of an amino acid or—NH(CH₂)_(p)-(amino acid);

[0238] (e) W is O, S, —N—CN, or —N—OR²;

[0239] (f) m is 1,2,3,4, or 5;

[0240] (g) p is 0, 1,2,3,4, or 5,and

[0241] (h) R^(2″), R^(3″), R^(4″), R^(5″), and R^(6″), are independently(i) hydrogen, (ii) halogen, (iii) NO₂, (iv) —CN, (v) —OR², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,(x) —C₁₋₅ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₅ thioether, or C₁₋₅ alkoxy,(xi) —C₁₋₅ alkoxy, (xii) —OH, or (ix) —NR²R².

[0242] In a first series of preferred subembodiments of the secondprincipal embodiment, Z is defined as follows:

[0243] 1) Z is C(W)NR²R³

[0244] 2) Z is C(O)NR²R³

[0245] 3) Z is C(O)NR²R³, and R² is hydrogen

[0246] 4) Z is C(O)NR²R³, R² is hydrogen, and R³ is NR²R²

[0247] 5) Z is C(O)NR²R³, R² is hydrogen, and R³ is NR²R², and R² isC₁₋₅ alkyl optionally substituted with OH

[0248] 6) Z is C(O)NR²R³, R² is hydrogen, and R³ is (CH₂)_(m)C(O)NR²R²

[0249] 7) Z is C(O)NR²R³, R² is hydrogen, and R³ is substituted orunsubstituted alkyl

[0250] 8) Z is C(O)NR²R³, R² is hydrogen, and R³ is alkyl substituted bysubstituted or unsubstituted aryl or heterocycle

[0251] 9) Z is C(O)R³, R³ is a residue of an amino acid or—NH(CH₂)_(p)-(amino acid)

[0252] 10) Z is —C(O)NH₂.

[0253] 11) Z is —C(O)NHNHC₂H₅OH

[0254] 12) Z is —C(O)NHCH₂C(O)NH₂

[0255] 13) Z is —C(O)NHCH₂CONHNH₂

[0256] 14) Z is —C(O)NHCH₂CH₂-(2NO₂,5Me imidazole)

[0257] 15) Z is —C(O)NHCH₂NHCH(CH₃)COOH

[0258] 16) Z is —C(O)CH═CHC(O)NH₂

[0259] A second series of preferred subembodiments of the secondprincipal embodiment is defined when R^(4′), R^(5′), R^(6′), R^(7′), aredefined as follows:

[0260] 1) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,or (x) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether,

[0261] 2) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,or (x) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether,

[0262] 3) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,or (x) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether,

[0263] 4) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², or (vi) C₁₋₃ alkyl oralkenyl optionally substituted with one or more of —OH, —SH, C(O)H,COOH, halogen, or NH₂,

[0264] 5) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², or (vi) C₁₋₃ alkyl oralkenyl optionally substituted with one or more of —OH, —SH, C(O)H,COOH, halogen, or NH₂,

[0265] 6) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², or (vi) C₁₋₃ alkyl oralkenyl optionally substituted with one or more of —OH, —SH, C(O)H,COOH, halogen, or NH₂,

[0266] 7) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are haloor C₁₋₃ alkyl or alkenyl substituted with one or more halo,

[0267] 8) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are haloor C₁₋₃ alkyl or alkenyl substituted with one or more halo,

[0268] 9) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are haloor C₁₋₃ alkyl or alkenyl substituted with one or more halo,

[0269] 10) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are Cl,F, CF₃, or vinyl bromide,

[0270] 11) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are Cl,F, CF₃, or vinyl bromide,

[0271] 12) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are Cl,F, CF₃, or vinyl bromide,

[0272] 13) R^(4′), R^(6′) and R^(7′) are hydrogen, and R^(5′) is (i)oxime, (ii) hydrazine, or (iii) C₁₋₃ alkyl or alkenyl optionallysubstituted with one or more of —OH, —SH, C(O)H, COOH, halogen, NR²R²,C₁₋₃ alkoxy, or C₁₋₃ thioether,

[0273] 14) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are Cl,

[0274] 15) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are Cl,

[0275] 16) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are F,

[0276] 17) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are F,

[0277] 18) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are F,

[0278] 19) R^(4′) and R^(7′) are hydrogen, and R^(5′) is Cl, and R^(6′)is F,

[0279] 20) R^(4′) and R^(7′) are hydrogen, and R^(5′) is Cl, and R^(6′)is CF₃,

[0280] 21) R^(4′), R^(6′), and R^(7′) are hydrogen, and R^(5′) is CF₃,

[0281] 22) R^(4′), R^(6′), and R^(7′) are hydrogen, and R^(5′) is vinylbromide.

[0282] A third series of preferred subembodiments of the secondprincipal embodiment are defined when R^(2″), R^(3″), R^(4″), R^(5″),and R^(6″), are defined as follows:

[0283] 1) R^(2″), R^(4″), and R^(6″), are hydrogen, and R^(3″) and R⁵are independently (i) halogen, (ii) NO₂, (iii) —CN, (iv) —OR², (v)—NHSO₂—C₁₋₃alkyl, (vi) —NHCO—C₁₋₃alkyl, (vii) oxime, (vii) hydrazine,(viii) —C₁₋₅ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₅ thioether, or C₁₋₅ alkoxy,(ix) —C₁₋₅ alkoxy, (x) —OH, or (xi) —NR²R²

[0284] 2) R^(2″), R^(4″), and R^(6″), are hydrogen, and R^(3″) andR^(5″) are independently (i) halogen, (ii) NO₂, (iii) —CN, (iv) —OR²,(v) —C₁₋₅ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, COOH, halogen, NR²R², C₁₋₅ thioether, or C₁₋₅ alkoxy, (vi)—C₁₋₅ alkoxy, (vii) —OH, or (viii) —NR²R²

[0285] 3) R^(2″), R^(4″), and R^(6″), are hydrogen, and R^(3″) andR^(5″) are independently (i) halogen, (ii) NO₂, (iii) —CN, (iv) —OR²,(v) —C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, COOH, halogen, or NH₂, (vi) —C₁₋₃ alkoxy, (vii) —OH, or (viii)—NR²R²

[0286] 4) R^(2″), R^(4″), and R^(6″), are hydrogen, and R^(3″) andR^(5″) are independently (i) halogen, or (ii) —C₁₋₃ alkyl or alkenyloptionally substituted with one or more halogen

[0287] 5) R^(2″), R^(3″), R^(4″), R^(5″), and R^(6″), are H

[0288] 6) R^(2″), R^(4″), and R^(6″), are H, and R^(3″) and R^(5″) aremethyl

[0289] 7) R^(2″), R^(4″), and R^(6″), are H, and R^(3″) and R^(5″) areCl

[0290] 8) R^(2″), R^(4″), and R^(6″), are H, and R^(3″) and R1 ″ are F

[0291] 9) R^(2″),R^(4″), and R^(6″), are H, and R^(3″) and R^(5″) areCF₃

[0292] A fourth series of preferred subembodiments of the secondprincipal embodiment are defined when Z is as defined in any one of thefirst series of preferred subembodiments of the second principalembodiment, R^(4′), R^(5′), R^(6′), and R^(7′) are as defined in any oneof the second series of preferred subembodiments of the second principalembodiment, and R^(2″), R^(3″), R^(4″), R^(5″), and R^(6″), are asdefined in the second principal embodiment.

[0293] A fifth series of preferred subembodiments are defined when Z isas defined in any one of the first series of preferred subembodiments ofthe second principal embodiment, R^(4′), R^(5′), R^(6′), and R^(7′) areas defined in the second principal embodiment, and R^(2″), R^(3″),R^(4″), R^(5″), and R^(6″), are as defined in any one of the thirdseries of preferred subembodiment of the second principal embodiment.

[0294] A sixth series of preferred subembodiments are defined when Z isas defined in the second principal embodiment, R^(4′), R^(5′), R^(6′),and R^(7′) are as defined in any one of the second series of preferredsubembodiments of the second principal embodiment, and R^(2″), R^(3″),R^(4″), R^(5″), and R^(6″), are as defined in any one of the thirdseries of preferred subembodiments of the second principal embodiment.

[0295] A seventh series of preferred subembodiments are defined when Zis as defined in any one of the first series of preferred subembodimentsof the second principal embodiment, R^(4′), R^(5′), R^(6′), and R^(7′)are as defined in any one of the second series of preferredsubembodiments of the second principal embodiment, and R^(2″), R^(3″),R^(4″), R^(5″), and R^(6″), are as defined in any one of the thirdseries of preferred subembodiments of the second principal embodiment.

[0296] In each of the subembodiments within the first, second, third,fourth, fifth, sixth, and seventh preferred series of subembodiments ofthe second principal embodiment, Y is preferably SO₂.

[0297] Preferred species of the second principal embodiment are definedwhen:

[0298] 1) Z is —C(O)NH₂, R^(4′) and R^(7′) are hydrogen, R^(5′) andR^(6′) are Cl, R^(2″), R^(3″), R^(4″), R^(5″), and R^(6″) are H, and Yis SO₂.

[0299] 2) Z is —C(O)NH₂, R^(4′) and R^(7′) are hydrogen, R^(5′) andR^(6′) are Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″) aremethyl, and Y is SO₂.

[0300] 3) Z is —C(O)NH₂, R^(4′) and R^(6′) are hydrogen, R^(5′) andR^(7′) are Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″) aremethyl, and Y is SO₂.

[0301] 4) Z is —C(O)NH₂, R^(6′) and R^(7′) are hydrogen, R^(4′) andR^(5′) are F, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″) aremethyl, and Y is SO₂.

[0302] 5) Z is —C(O)NH₂, R^(4′) and R^(7′) are hydrogen, R^(5′) andR^(6′) are F, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″) aremethyl, and Y is SO₂.

[0303] 6) Z is —C(O)NH₂, R^(4′) and R^(6′) are hydrogen, R^(5′) andR^(7′) are F, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″) aremethyl, and Y is SO₂.

[0304] 7) Z is —C(O)NH₂, R^(4′) and R^(7′) are hydrogen, R^(5′) is Cl,and R^(6′) is F, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″)are methyl, and Y is SO₂.

[0305] 8) Z is —C(O)NH₂, R^(4′) and R^(7′) are hydrogen, R^(5′) is Cl,and R^(6′) is CF₃, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″)are methyl, and Y is SO₂.

[0306] 9) Z is —C(O)NH₂, R^(4′), R^(6′), and R^(7′) are hydrogen, R^(5′)is CF₃, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″) are methyl,and Y is SO₂.

[0307] 10) Z is —C(O)NH₂, R^(4′), R^(6′), and R^(7′) are hydrogen,R^(5′) is vinyl bromide, R^(2″), R^(4″), and R^(6″), are H, R^(3″) andR^(5″) are methyl, and Y is SO₂.

[0308] A third principal embodiment of the invention compound (I) isdefined as follows:

[0309] (a) Z is (i) C(W)NR²R³, (ii) —COR³, (iii) —COOR³, (iv)—CR²R²—S(O)_(n)—R³, (v) —CR²R²NHR², (vi) —CR²R²—CO—R³, (vii) substitutedor unsubstituted lower alkyl, or (viii) —CN;

[0310] (i) R² is hydrogen, or C₁₋₅ alkyl optionally substituted with—OH, or NR²R²,

[0311] (b) R³ is (i) substituted or unsubstituted alkyl, alkenyl, aryl,or heterocycle, (ii) —C₁₋₅ alkoxy, (iii) —OH, (iv) hydrogen, (v) —NR²R²,(vi) —(CH₂)_(m)C(O)NR²R², or (vii) a residue of an amino acid or—NH(CH₂)_(p)-(amino acid);

[0312] (c) W is O, S, —N—CN, or —N—OR²;

[0313] (d) mis 1, 2, 3, 4, or 5;

[0314] (e) pis0, 1, 2, 3, 4, or 5;

[0315] (f) R^(4′), R^(5′), R^(6′), R^(7′), are independently (i) H,(ii), halo, (iii) —NO₂, (iv) —CN, (v) —OR², (vi) —NR²R², (vii)—NHSO₂—C₁₋₃alkyl, (viii) —NHCO—C₁₋₃alkyl, (ix) oxime, (x) hydrazine, or(xi) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether;and

[0316] (g) R^(2″), R^(3″), R^(4″), R^(5″), and R^(6″), are independently(i) hydrogen, (ii) halogen, (iii) NO₂, (iv) —CN, (v) —OR², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,(x) —C₁₋₅ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₅ thioether, or C₁₋₅ alkoxy,(xi) —C₁₋₅ alkoxy, (xii) —OH, or (ix) —NR²R², wherein (i) at least 2 ofR^(2″), R^(3″), R^(4″), R^(5″), and R^(6″) are not hydrogen, or (ii) atleast 1 of R^(2″), R^(3″), R^(4″), R^(5″), and R^(6″) is not hydrogen,halogen, or OR².

[0317] A first series of preferred subembodiments of the third principalembodiment are defined when Z is as follows:

[0318] 1) Z is C(W)NR²R³

[0319] 2) Z is C(O)NR²R³

[0320] 3) Z is C(O)NR²R³, and R² is hydrogen

[0321] 4) Z is C(O)NR²R³, R² is hydrogen, and R³ is NR²R²

[0322] 5) Z is C(O)NR²R³, R² is hydrogen, and R³ is NR²R², and R² isC₁₋₅ alkyl optionally substituted with OH

[0323] 6) Z is C(O)NR²R³, R² is hydrogen, and R³ is (CH₂)_(m)C(O)NR²R²

[0324] 7) Z is C(O)NR²R³, R² is hydrogen, and R³ is substituted orunsubstituted alkyl

[0325] 8) Z is C(O)NR²R³, R² is hydrogen, and R³ is alkyl substituted bysubstituted or unsubstituted aryl or heterocycle

[0326] 9) Z is C(O)R³, R³ is a residue of an amino acid or—NH(CH₂)_(p)-(amino acid)

[0327] 10) Z is —C(O)NH₂.

[0328] 11) Z is —C(O)NHNHC₂H₅OH

[0329] 12) Z is —C(O)NHCH₂C(O)NH₂

[0330] 13) Z is —C(O)NHCH₂CONHNH₂

[0331] 14) Z is —C(O)NHCH₂CH₂-(2NO₂, 5Me imidazole) 15) Z is—C(O)NHCH₂NHCH(CH₃)COOH 16) Z is —C(O)CH═CHC(O)NH₂

[0332] A second series of preferred embodiments of the second principalembodiment is defined when R^(4′), R^(5′), R^(6′), and R^(7′) aredefined as follows:

[0333] 1) R^(4′), R^(6′), and R^(7′) are hydrogen, and R^(5′) is (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,or (x) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or CI₃ thioether,

[0334] 2) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,or (x) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether,

[0335] 3) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,or (x) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether,

[0336] 4) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², (vi)—NHSO₂—C₁₋₃alkyl, (vii) —NHCO—C₁₋₃alkyl, (viii) oxime, (ix) hydrazine,or (x) C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₃alkoxy, or C₁₋₃ thioether,

[0337] 5) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², or (vi) C₁₋₃ alkyl oralkenyl optionally substituted with one or more of —OH, —SH, C(O)H,COOH, halogen, or NH₂,

[0338] 6) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are (i),halo, (ii) —NO₂, (iii) —CN, (ivOR², (v) —NR²R², or (vi) C₁₋₃ alkyl oralkenyl optionally substituted with one or more of —OH, —SH, C(O)H,COOH, halogen, or NH₂,

[0339] 7) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are (i),halo, (ii) —NO₂, (iii) —CN, (iv) —OR², (v) —NR²R², or (vi) C₁₋₃ alkyl oralkenyl optionally substituted with one or more of —OH, —SH, C(O)H,COOH, halogen, or NH₂,

[0340] 8) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are haloor C₁₋₃ alkyl or alkenyl substituted with one or more halo,

[0341] 9) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are haloor C₁₋₃ alkyl or alkenyl substituted with one or more halo,

[0342] 10) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) arehalo or C₁₋₃ alkyl or alkenyl substituted with one or more halo,

[0343] 11) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are Cl,F, CF₃, or vinyl bromide

[0344] 12) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are Cl,F, CF₃, or vinyl bromide

[0345] 13) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are Cl,F, CF₃, or vinyl bromide

[0346] 14) R^(4′), R^(6′) and R^(7′) are hydrogen, and R^(5′) is (i)oxime, (ii) hydrazine, or (iii) C₁₋₃ alkyl or alkenyl optionallysubstituted with one or more of —OH, —SH, C(O)H, COOH, halogen, NR²R²,C₁₋₃ alkoxy, or C₁₋₃ thioether

[0347] 15) R^(4′), R^(6′), and R^(7′) are hydrogen, and R^(5′) is Cl

[0348] 16) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are Cl

[0349] 17) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are Cl

[0350] 18) R^(6′) and R^(7′) are hydrogen, and R^(4′) and R^(5′) are F

[0351] 19) R^(4′) and R^(7′) are hydrogen, and R^(5′) and R^(6′) are F

[0352] 20) R^(4′) and R^(6′) are hydrogen, and R^(5′) and R^(7′) are F

[0353] 21) R^(4′) and R^(7′) are hydrogen, and R^(5′) is Cl, and R^(6′)is F

[0354] 22) R^(4′) and R^(7′) are hydrogen, and R^(5′) is Cl, and R^(6′)is CF₃

[0355] 23) R^(4′), R^(6′), and R^(7′) are hydrogen, and R^(5′) is CF₃

[0356] 24) R^(4′), R^(6′), and R^(7′) are hydrogen, and R^(5′) is vinylbromide

[0357] A third series of preferred subembodiments of the third principalembodiment is defined when R^(2″), R^(3″), R^(4″), R^(5″), and R^(6″)are defined as follows:

[0358] 1) R^(2″), R^(4″), and R^(6″), are hydrogen, and R^(3″) andR^(5″) are independently (i) halogen, (ii) NO₂, (iii) —CN, (iv) —OR²,(v) —NHSO₂—C₁₋₃alkyl, (vi) —NHCO—C₁₋₃alkyl, (vii) oxime, (vii)hydrazine, (viii) —C₁₋₅ alkyl or alkenyl optionally substituted with oneor more of —OH, —SH, C(O)H, COOH, halogen, NR²R², C₁₋₅ thioether, orC₁₋₅ alkoxy, (ix) —C₁₋₅ alkoxy, (x) —OH, or (xi) —NR²R²

[0359] 2) R^(2″), R^(4″), and R^(6″), are hydrogen, and R^(3″) andR^(5″) are independently (i) halogen, (ii) NO₂, (iii) —CN, (iv) —OR²,(v) —C₁₋₅ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, COOH, halogen, NR²R², C₁₋₅ thioether, or C₁₋₅ alkoxy, (Vi)—C₁₋₅ alkoxy, (vii) —OH, or (viii) —NR²R²

[0360] 3) R^(2″), R^(4″), and R^(6″), are hydrogen, and R^(3″) andR^(5″) are independently (i) halogen, (ii) NO₂, (iii) —CN, (iv) —OR²,(v) —C₁₋₃ alkyl or alkenyl optionally substituted with one or more of—OH, —SH, COOH, halogen, or NH₂, (vi) —C₁₋₃ alkoxy, (vii) —OH, or (viii)—NR²R²

[0361] 4) R^(2″), R^(4″), and R^(6″), are hydrogen, and R^(3″) andR^(5″) are independently (i) halogen, or (ii) —C₁₋₃ alkyl or alkenyloptionally substituted with one or more halogen

[0362] 5) R^(2″), R^(4″), and R^(6″), are H, and R^(3″) and R^(5″) aremethyl

[0363] 6) R^(2″), R^(4″), and R^(6″), are H, and R^(3″) and R^(5″) areCl

[0364] 7) R^(2″), R^(4″), and R^(6″), are H, and R^(3″) and R^(5″) are F

[0365] 8) R^(2″), R^(4″), and R^(6″), are H, and R^(3″) and R^(5″) areCF₃

[0366] A fourth series of preferred subembodiments of the thirdprincipal embodiment are defined when Z is as defined in any one of thefirst series of preferred subembodiments of the third principalembodiment, R^(4′), R^(5′), R^(6′), and R^(7′) are as defined in any oneof the second series of preferred subembodiments of the third principalembodiment, and R^(2″), R^(3″), R^(4″), R^(5″), and R^(6″), are asdefined in the third principal embodiment.

[0367] A fifth series of preferred subembodiments are defined when Z isas defined in any one of the first series of preferred subembodiments ofthe third principal embodiment, R^(4′), R^(5′), R^(6′), and R^(7′) areas defined in the third principal embodiment, and R^(2″), R^(3″),R^(4″), R^(5″), and R^(6″), are as defined in any one of the thirdseries of preferred subembodiment of the third principal embodiment.

[0368] A sixth series of preferred subembodiments are defined when Z isas defined in the third principal embodiment, R^(4′), R^(5′), R^(6′),and R^(7′) are as defined in any one of the second series of preferredsubembodiments of the third principal embodiment, and R^(2″), R^(3″),R^(4″), R^(5″), and R^(6″), are as defined in any one of the thirdseries of preferred subembodiments of the third principal embodiment.

[0369] A seventh series of preferred subembodiments are defined when Zis as defined in any one of the first series of preferred subembodimentsof the third principal embodiment, R^(4′), R^(5′), R^(6′), and R^(7′)are as defined in any one of the second series of preferredsubembodiments of the third principal embodiment, and R^(2″), R^(3″),R^(4″), R^(5″), and R^(6″), are as defined in any one of the thirdseries of preferred subembodiments of the third principal embodiment.

[0370] In each of the subembodiments within the first, second, third,fourth, fifth, sixth, and seventh preferred series of subembodiments ofthe third principal embodiment, Y is preferably SO₂.

[0371] Preferred species of the third principal embodiment are definedas follows:

[0372] 1) Z is —C(O)NHNHC₂H₅OH, R^(4′), R^(6′), and R^(7′) are hydrogen,R^(5′) is Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(″) aremethyl, and Y is SO₂;

[0373] 2) Z is —C(O)NHCH₂C(O)NH₂, R^(4′), R^(6′), and R^(7′) arehydrogen, R^(5′) is Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) andR^(5″) are methyl, and Y is SO₂;

[0374] 3) Z is —C(O)NHCH₂CONHNH₂, R^(4′), R^(6′), and R^(7′) arehydrogen, R^(5′) is Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) andR^(5″) are methyl, and Y is SO₂;

[0375] 4) Z is —C(O)NHCH₂CH₂—(2NO₂, 5Me imidazole), R^(4′), R^(6′), andR^(7′) are hydrogen, R^(5′) is Cl, R^(2″), R^(4″), and R^(6″), are H,R^(3″) and R^(5″) are methyl, and Y is SO₂;

[0376] 5) Z is —C(O)NHCH₂NHCH(CH₃)COOH, R^(4′)′, R^(6′), and R^(7′) arehydrogen, R^(5′) is Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) andR^(5′) are methyl, and Y is SO₂; and

[0377] 6) Z is —C(O)CH═CHC(O)NH₂, R^(4′), R^(6′), and R^(7′) arehydrogen, R^(5′) is Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) andR^(5″) are methyl, and Y is SO₂.

[0378] 7) Z is —C(O)NH₂, R^(4′) and R^(7′) are hydrogen, R^(5′) andR^(6′) are Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″) aremethyl, and Y is SO_(2.)

[0379] 8) Z is —C(O)NH₂, R^(4′) and R^(6′) are hydrogen, R^(5′) andR^(7′) are Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″) aremethyl, and Y is SO₂.

[0380] 9) Z is —C(O)NH₂, R^(6′) and R^(7′) are hydrogen, R^(4′) andR^(5′) are F, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R⁵ aremethyl, and Y is SO₂.

[0381] 10) Z is —C(O)NH₂, R^(4′) and R^(7′) are hydrogen, R^(5′) andR^(6′) are F, R^(2″), R⁴, and R^(6″), are H, R^(3″) and R^(5″) aremethyl, and Y is SO_(2.)

[0382] 11) Z is —C(O)NH₂, R^(4′) and R^(6′) are hydrogen, R^(5′) andR^(7′) are F, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″) aremethyl, and Y is SO₂.

[0383] 12) Z is —C(O)NH₂, R^(4′) and R^(7′) are hydrogen, R^(5′) is Cl,and R^(6′) is F, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″)are methyl, and Y is SO₂.

[0384] 13) Z is —C(O)NH₂, R^(4′) and R^(7′) are hydrogen, R^(5′) is Cl,and R^(6′) is CF₃, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″)are methyl, and Y is SO₂.

[0385] 14) Z is —C(O)NH₂, R^(4′), R^(6′), and R^(7′) are hydrogen,R^(5′) is CF₃, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″) aremethyl, and Y is SO₂.

[0386] 15) Z is —C(O)NH₂, R^(4′), R^(6′), and R^(7′) are hydrogen,R^(5′) is vinyl bromide, R^(2″), R^(4″), and R^(6″), are H, R^(3″) andR^(5″) are methyl, and Y is SO₂.

[0387] 16) Z is —C(O)NH₂, R^(4′), R^(6′), and R^(7′) are hydrogen,R^(5′) is Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″) areCF₃, and Y is SO₂.

[0388] 17) Z is —C(O)NH₂, R^(4′), R^(6′), and R^(7′) are hydrogen,R^(5′) is Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″) areF, and Y is SO₂.

[0389] 18) Z is —C(O)NH₂, R^(4′), R^(6′), and R^(7′) are hydrogen,R^(5′) is Cl, R^(2″), R^(4″), and R^(6″), are H, R^(3″) and R^(5″) areCl, and Y is SO₂.

[0390] In a particular embodiment, the phenylindole is a compound of thestructure:

[0391] or a pharmaceutically acceptable salt or prodrug thereof.

[0392] In another particular embodiment, the phenylindole is a compoundof the structure:

[0393] or a pharmaceutically acceptable salt or prodrug thereof.

[0394] In yet another particular embodiment, the phenylindole is acompound of the structure:

[0395] or a pharmaceutically acceptable salt or prodrug thereof.

[0396] In yet another particular embodiment, the phenylindole is acompound of the structure:

[0397] or a pharmaceutically acceptable salt or prodrug thereof.

[0398] In another particular embodiment, the phenylindole is a compoundof the structure:

[0399] or a pharmaceutically acceptable salt or prodrug thereof.

[0400] In yet another particular embodiment of the present invention,the phenylindole is a compound of the structure:

[0401] or a pharmaceutically acceptable salt or prodrug thereof.

[0402] In yet another particular embodiment of the present invention,the phenylindole is a compound of the structure:

[0403] or a pharmaceutically acceptable salt or prodrug thereof.

[0404] In yet another particular embodiment of the present invention,the phenylindole is a compound of the structure:

[0405] or a pharmaceutically acceptable salt or prodrug thereof.

[0406] The phenylindoles of this invention belong to a class of anti-HIVagents that inhibit HIV reverse transcriptase activity. Compounds can bescreened for their ability to inhibit HIV reverse transcriptase activityin vitro according to screening methods set forth more particularlyherein. One can readily determine the spectrum of activity by evaluatingthe compound in the assays described herein or with another confirmatoryassay.

[0407] In one embodiment the efficacy of the anti-HIV compound ismeasured according to the concentration of compound necessary to reducethe plaque number of the virus in vitro, according to methods set forthmore particularly herein, by 50% (i.e. the compound's EC₅₀). Inpreferred embodiments the compound exhibits an EC₅₀ of less than 15 or10 micromolar.

[0408] The active compound can be administered as any salt or prodrugthat upon administration to the recipient is capable of providingdirectly or indirectly the parent compound, or that exhibits activityitself. Nonlimiting examples are the pharmaceutically acceptable salts(alternatively referred to as “physiologically acceptable salts”).Further, the modifications can affect the biological activity of thecompound, in some cases increasing the activity over the parentcompound. This can easily be assessed by preparing the salt or prodrugand testing its antiviral activity according to the methods describedherein, or other methods known to those skilled in the art.

[0409] II. Pharmaceutically Acceptable Salts and Prodrugs

[0410] The term “pharmaceutically acceptable salt or prodrug” is usedthroughout the specification to describe any pharmaceutically acceptableform (such as an ester, amide, salt of an ester, salt of an amide or arelated group) of a compound that, upon administration to a patient,provides the active compound. As used herein, the term pharmaceuticallyacceptable salts refers to salts that retain the desired biologicalactivity of the herein-identified compounds and exhibit minimalundesired toxicological effects. Pharmaceutically acceptable saltsinclude those derived from pharmaceutically acceptable inorganic ororganic acids and bases. Non-limiting examples of suitable salts includethose derived from inorganic acids such as, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid,bicarbonic acid, carbonic acid and the like, and salts formed withorganic acids such as amino acid, acetic acid, oxalic acid, tartaricacid, succinic acid, malic acid, malonic acid, ascorbic acid, citricacid, benzoic acid, tannic acid, palmoic acid, alginic acid,polyglutamic acid, tosic acid, methanesulfonic acid, naphthalenesulfonicacid, naphthalenedisulfonic acid, o-ketoglutaric acid,α-glycerophosphoric acid and polygalacturonic acid. Suitable saltsinclude those derived from alkali metals such as lithium, potassium andsodium, alkaline earth metals such as calcium and magnesium, amongnumerous other acids well known in the pharmaceutical art. Othersuitable salts include those derived from other metal cations such aszinc, bismuth, barium, aluminum, copper, cobalt, nickel, cadmium, andthe like, or with a cation formed from an amine, such as ammonia,N,N-dibenzylethylene-diamine, D-glucosamine, tetraethylammonium, orethylenediamine. Further, suitable salts include those derived from acombinations of acids and bases, for example, a zinc tannate salt or thelike.

[0411] Pharmaceutically acceptable prodrugs refer to a compound that ismetabolized, for example hydrolyzed or oxidized, in the host to form thecompound of the present invention. Typical examples of prodrugs includecompounds that have biologically labile protecting groups on afunctional moiety of the active compound. Prodrugs include compoundsthat can be oxidized, reduced, aminated, deaminated, hydroxylated,dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated,acylated, deacylated, phosphorylated, dephosphorylated to produce theactive compound. The compounds of this invention either possessantiviral activity against HIV, or are metabolized to a compound thatexhibits such activity.

[0412] Any of the phenylindoles described herein can be administered asa prodrug to increase the activity, bioavailability, stability orotherwise alter the properties of the phenylindole. A number of prodrugligands are known. In general, alkylation, acylation or other lipophilicmodification of a heteroatom of the phenylindole will increase thestability of the compound. Examples of substituent groups that canreplace one or more hydrogens on a heterocycle include, but are notlimited to alkyl, aryl, steroids, carbohydrates, including sugars,1,2-diacylglycerol, phospholipids, phosphotidylcholine, phosphocholineand alcohols. Any of these can be used in combination with the disclosedphenylindoles to achieve a desired effect.

[0413] III. Definitions

[0414] The following definitions and term construction are intended,unless otherwise indicated.

[0415] Specific and preferred values listed below for radicals,substituents and ranges, are for illustration only; they do not excludeother defined values or other values within defined ranges for theradicals and substituents.

[0416] Halo is fluoro, chloro, bromo, or iodo.

[0417] Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight andbranched groups; but reference to an individual radical such as “propyl”embraces only the straight chain radical, a branched chain isomer suchas “isopropyl” being specifically referred to.

[0418] The term alkyl, as used herein, unless otherwise specified,refers to a saturated straight, branched, or cyclic, primary, secondary,or tertiary hydrocarbon of C₁ to C₁₀, and specifically includes methyl,ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, _(t)-butyl,pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl,cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and2,3-dimethylbutyl. When the context of this document allows alkyl to besubstituted, the moieties with which the alkyl group can be substitutedare selected from the group consisting of hydroxyl, amino, alkylamino,arylamino, alkoxy, aryloxy, aryl, heterocycle, halo, carboxy, acyl,acyloxy, amido, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,phosphate, or phosphonate, either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin Greene, et al., Protective Groups in Organic Synthesis, John Wileyand Sons, Second Edition, 1991, hereby incorporated by reference.

[0419] The term lower alkyl, as used herein, and unless otherwisespecified, refers to a C₁ to C₄ saturated straight, branched, or ifappropriate, a cyclic (for example, cyclopropyl) alkyl group, includingboth substituted and unsubstituted forms. Unless otherwise specificallystated in this application, when alkyl is a suitable moiety, lower alkylis preferred. Similarly, when alkyl or lower alkyl is a suitable moiety,unsubstituted alkyl or lower alkyl is preferred.

[0420] The terms alkenyl and alkynyl refer to alkyl moieties, includingboth substituted and substituted forms, wherein at least one saturatedC—C bond is replaced by a double or triple bond. Thus, (C₂-C₆)alkenylcan be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl. Similarly, (C₂-C₆)alkynylcan be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, or 5-hexynyl.

[0421] The term “alkylene” refers to a saturated, straight chain,divalent alkyl radical of the formula —(CH₂)_(n)—, wherein n can be 1,2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0422] As used herein, with exceptions as noted, “aryl” is intended tomean any stable monocyclic, bicyclic or tricyclic carbon ring of up to 8members in each ring, wherein at least one ring is aromatic as definedby the Huckel 4n+2 rule. Examples of aryl ring systems include phenyl,naphthyl, tetrahydronaphthyl, and biphenyl. The aryl group can besubstituted with one or more moieties selected from the group consistingof hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, alkyl,heterocycle, halo, carboxy, acyl, acyloxy, amido, nitro, cyano, sulfonicacid, sulfate, phosphonic acid, phosphate, or phosphonate, eitherunprotected, or protected as necessary, as known to those skilled in theart, for example, as taught in Greene, et al., Protective Groups inOrganic Synthesis, John Wiley and Sons, Second Edition, 1991.

[0423] The term heterocycle or heterocyclic, as used herein except wherenoted represents a stable 5- to 7-membered monocyclic or stable 8- to11-membered bicyclic heterocyclic ring which is either saturated orunsaturated, including heteroaryl, and which consists of carbon atomsand from one to three heteroatoms selected from the group consisting ofN, O, S, and P; and wherein the nitrogen and sulfur heteroatoms mayoptionally be oxidized, and the nitrogen heteroatom may optionally bequatemized, and including any bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any heteroatom or carbon atom whichresults in the creation of a stable structure.

[0424] Nonlimiting examples of heteroaryl and heterocyclic groupsinclude furyl, fuiranyl, pyridyl, pyrimidyl, thienyl, isothiazolyl,imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl,quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl,isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl,cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan,pyrrole, isopyrrole, pyrazole, imidazole, 1,2,3-triazole,1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, pyrimidine orpyridazine, and pteridinyl, aziridines, thiazole, isothiazole,1,2,3-oxadiazole, thiazine, pyridine, pyrazine, piperazine, pyrrolidine,oxaziranes, phenazine, phenothiazine, morpholinyl, pyrazolyl,pyridazinyl, pyrazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl,pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl,imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine,N6-alkylpurines, N6-benzylpurine, N6-halopurine, N6-vinypurine,N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine,N6-thioalkyl purine, thymine, cytosine, 6-azapyrimidine,2-mercaptopyrmidine, uracil, N5-alkyl-pyrimidines, N5-benzylpyrimidines,N5-halopyrimidines, N5-vinyl-pyrimidine, N5-acetylenic pyrimidine,N5-acyl pyrimidine, N5-hydroxyalkyl purine, and N6-thioalkyl purine, andisoxazolyl. The heteroaromatic and heterocyclic moieties can beoptionally substituted as described above for aryl, includingsubstituted with one or more substituents selected from hydroxyl, amino,alkylamino, arylamino, alkoxy, aryloxy, alkyl, heterocycle, halo,carboxy, acyl, acyloxy, amido, nitro, cyano, sulfonic acid, sulfate,phosphonic acid, phosphate, or phosphonate, either unprotected, orprotected as necessary, as known to those skilled in the art, forexample, as taught in Greene, et al., Protective Groups in OrganicSynthesis, John Wiley and Sons, Second Edition, 1991.

[0425] The heteroaromatic can be partially or totally hydrogenated asdesired. As a nonlimiting example, dihydropyridine can be used in placeof pyridine. Functional oxygen and nitrogen groups on the heteroarylgroup can be protected as necessary or desired. Suitable protectinggroups are well known to those skilled in the art, and includetrimethylsilyl, dimethylhexylsilyl, _(t)-butyldi-methylsilyl, and_(t)-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups,acyl groups such as acetyl and propionyl, methanesulfonyl, andp-toluenesulfonyl.

[0426] The term acyl refers to a compound of formula RC(O)—, wherein Ris substituted or unsubstituted alkyl or aryl, as defined herein. Theterm carboxyl refers to a compound of the formula —C(O)OR, wherein R issubstituted or unsubstituted alkyl or aryl, as defined herein.

[0427] The term aralkyl, as used herein, and unless otherwise specified,refers to an aryl group as defined above linked to the molecule throughan alkyl group as defined above. The term alkaryl, as used herein, andunless otherwise specified, refers to an alkyl group as defined abovelinked to the molecule through an aryl group as defined above.

[0428] The term alkoxy, as used herein, and unless otherwise specified,refers to a moiety of the structure —O-alkyl, wherein alkyl is asdefined above.

[0429] The term amino, as used herein, refers to a moiety represented bythe structure —NR₂, and includes primary amines, and secondary, andtertiary amines substituted by alkyl, aryl, heterocycle, acyl, andsulfinylalkyl. Thus, R₂ may represent two hydrogens, two alkyl moieties,or one hydrogen and one alkyl moiety.

[0430] The term amido, as used herein, refers to a moiety represented bythe structure —C(O)NR₂, wherein R₂ is as defined for amino.

[0431] As used herein, an “amino acid” is a natural amino acid residue(e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, LeuLys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, or anunnatural amino acid (e.g. phosphoserine; phosphothreonine;phosphotyrosine; gamma-carboxyglutamate; hippuric acid;octahydroindole-2-carboxylic acid; statine;1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid; penicillamine;ornithine; citrulline; a-methyl-alanine; para-benzoylphenylalanine;phenylglycine; propargyl-glycine; sarcosine; and tert-butylglycine)residue having one or more open valences. Other unnatural amino acidsinclude those represented by the formula NH₂ (CH₂)_(y) COOH, whereiny=2-20, and preferably 2-12, and include the aminoalkanoic acids such asε-amino caproic acid (H₂N—(CH₂)₅—COOH).

[0432] The term also comprises natural and unnatural amino acids bearingamino protecting groups such as acetyl, acyl, trifluoroacetyl, andbenzyloxycarbonyl), as well as natural and unnatural amino acidsprotected at carboxy with protecting groups such as a C₁-C₆ alkyl,phenyl or benzyl ester and amide. Other suitable amino and carboxyprotecting groups are known to those skilled in the art. See forexample, T. W. Greene, Protecting Groups in Organic Synthesis; Wiley:New York, 1981; D. Voet, Biochemistry, Wiley: New York, 1990; L. Stryer,Biochemistry, (3^(rd) Ed), W. H. Freeman and Co.: New York, 1975; J.March, Advanced Organic Chemistry, Reactions, Mechanisms and Structure,(2^(nd) Ed.), McGraw Hill: New York, 1977; F. Carey and R. Sundberg,Advanced Organic Chemistry, Part B: Reactions and Synthesis, (2^(nd)Ed.), Plenum: New York, 1977; and references cited therein.

[0433] As used herein, a “retrovirus” includes any virus that expressesreverse transcriptase. Examples of a retrovirus include, but are notlimited to, HIV-1, HIV-2, HTLV-I, HTLV-II, FeLV, FIV, SIV, AMV, MMTV,and MoMuLV.

[0434] As used herein, “reverse transcriptase (RT)” refers to an enzymehaving an NNI binding site similar to that of HIV-1 RT and to whichligands which bind the composite binding pocket of the invention bind.One means by which RT activity can be determined is by measuring viralreplication. One measure of HIV-1 viral replication is the p24 coreantigen enzyme immunoassay, for example, using the assay commerciallyavailable from Coulter Corporation/Immunotech, Inc. (Westbrooke, Mich.).Another means by which RT activity is analyzed is by assay ofrecombinant HIV-1 reverse transcriptase (rRT) activity, for example,using the Quan-T—RT assay system commercially available from Amersham(Arlington Heights, Ill.) and described in Bosworth, et al., Nature1989, 341:167-168.

[0435] As used herein, a compound that “inhibits replication of humanimmunodeficiency virus (HIV)” means a compound that, when contacted withHIV-1, for example, via HIV-infected cells, effects a reduction in theamount of HIV-1 as compared with untreated control. Inhibition ofreplication of HIV-1 can be measured by various means known in the art,for example, the p24 assay disclosed herein.

[0436] As used herein, a compound that is useful in “salvage therapy,”means a compound that can be taken with any regimen after a patient'sinitial treatment regimen has failed.

[0437] The term host, as used herein, refers to an unicellular ormulticellular organism in which the virus can replicate, including celllines and animals, and preferably a human. Alternatively, the host canbe carrying a part of the HIV genome, whose replication or function canbe altered by the compounds of the present invention. The term hostspecifically refers to infected cells, cells transfected with all orpart of the HIV genome and animals, in particular, primates (includingchimpanzees) and humans. In most animal applications of the presentinvention, the host is a human patient. Veterinary applications, incertain indications, however, are clearly anticipated by the presentinvention (such as chimpanzees).

[0438] IV. Combination or Alternation Therapy

[0439] In a preferred but not necessary embodiment, phenylindoles of thepresent invention is administered in combination or alternation withanother anti-HIV agent. In one embodiment the effect of administrationof the two or more agents in combination or alternation is synergistic.

[0440] Drug resistance most typically occurs by mutation of a gene thatencodes for an enzyme used in the viral replication cycle, and mosttypically in the case of HIV, in either the reverse transcriptase orprotease genes. It has been demonstrated that the efficacy of a drugagainst HIV infection can be prolonged, augmented, or restored byadministering the compound in combination or alternation with a second,and perhaps third, antiviral compound that induces a differentmutation(s) from that selected for by the principle drug. Alternatively,the pharmacokinetics, biodistribution or other parameter of the drug canbe altered by such combination or alternation therapy. In general,combination therapy is typically preferred over alternation therapybecause it induces multiple simultaneous stresses on the virus.

[0441] The second antiviral agent for the treatment of HIV, in oneembodiment, can be a protease inhibitor, a reverse transcriptaseinhibitor (a “RTI”), which can be either a synthetic nucleoside reversetranscriptase inhibitor (a “NRTI”) or a non-nucleoside reversetranscriptase inhibitor (a “NNRTI”), and HIV-integrase inhibitor, or achemokine inhibitor. In other embodiments, the second (or third)compound can be a pyrophosphate analog, or a fusion binding inhibitor. Alist compiling resistance data collected in vitro and in vivo for anumber of antiviral compounds is found in Schinazi et al., Mutations inretroviral genes associated with drug resistance, InternationalAntiviral News, Volume 5 (8), International Medical Press 1997.

[0442] In preferred embodiments, the phenylindole is administered incombination or alternation with FTC(2′,3′-dideoxy-3′-thia-5-fluorocytidine); 141W94 (amprenavir,GlaxoWellcome, Inc.); Viramune (nevirapine), Rescriptor (delavirdine);DMP-266 (efavirenz), DDI (2′,3′-dideoxyinosine); 3TC(3′-thia-2′,3′-dideoxycytidine); or DDC (2′,3′-dideoxycytidine). Inanother preferred embodiment, the phenylindole is administered incombination or alternation with abacavir (1592U89), which is(1S,4R)-4-[2-amino-6-cyclopropyl-amino)-9H-purin-9-yl]-2-cyclopentene-1-methanolsuccinate, D4T or AZT.

[0443] Other examples of antiviral agents that can be used incombination or alternation with the compounds disclosed herein for HIVtherapy include 3TC; foscarnet; carbovir, acyclovir, interferon,stavudine, and β-D-dioxolane nucleosides such as β-D-dioxolanylguanine(DXG), β-D-dioxolanyl-2,6-diaminopurine (DAPD), andβ-D-dioxolanyl-6-chloropurine (ACP).

[0444] Preferred protease inhibitors include indinavir ({1 (1,S,2R),5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2-hydroxy-1H-inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl)-D-erythro-pentoamidesulfate; Merck), nelfinavir (Agouron), ritonavir (Abbott), saquinavir(Roche) and DMP-450{[4R-4(r-a,5-a,6-b,7-6)]-hexahydro-5,6-bis(hydroxy)-1,3-bis(3-amino)phenyl]methyl)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one}-bismesylate(Triangle Pharmaceuticals, Inc.).

[0445] Nonlimiting examples of other compounds that can be administeredin combination or alternation with the phenylindole to augment theproperties of the drug on administration include abacavir:(1S,4R)-4-[2-amino-6-cyclopropyl-amino)-9H-purin-9-yl]-2-cyclopentene-1-methanol succinate (1592U89, a carbovir analog;GlaxoWellcome); BILA 1906:N-{1S-[[[3-[2S-{(1,1-dimethylethyl)amino]carbonyl}-4R-]3-pyridinylmethyl)thio]-1-piperidinyl]-2R-hydroxy-1S-(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl}-2-quinolinecarboxamide(Bio Mega/Boehringer-Ingelheim); BILA 2185:N-(1,1-dimethylethyl)-1-[2S-[[2-2,6-dimethyl-phenoxy)-1-oxoethyl]amino]-2R-hydroxy-4-phenylbutyl]4R-pyridinylthio)-2-piperidine-carboxamide(Bio Mega/Boehringer-Ingelheim); BM+51.0836:triazoloiso-indolinonederivative; BMS 186,318: aminodiol derivative HIV-1 protease inhibitor(Bristol-Myers-Squibb); d4API:9-[2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]-adenine (Gilead);stavudine: d4T, 2′,3′-dide-hydro-3′-deoxythymidine(Bristol-Myers-Squibb); HBY097:S-4-isopropoxycarbonyl-6-methoxy-3-(methylthio-methyl)-3,4-dihydroquinoxalin-2(1H)-thione; HEPT: 1-[(2-hydroxy-ethoxy)methyl]6-(phenylthio)-thymine;KNI-272: (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid-containingtripeptide; L-697,593; 5-ethyl-6-methyl-3-(2-phthalimido-ethyl)pyridin-2(1H)-one; L-735,524: hydroxy-aminopentane amide HIV-1 protease inhibitor(Merck); L-697,661:3-{[(-4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino}-5-ethyl-6-methylpyridin-2(1H)-one; L-FDDC: (−)-β-L-5-fluoro-2′,3′-dideoxycytidine; L-FDOC:(−)-β-L-5-fluoro-dioxolane cytosine; nevirapine:11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyridol-[3,2-b:2′,3′-e]diazepin-6-one(Boehringer-Ingelheim); PFA: phosphonoformate (foscamet; Astra); PMEA:9-(2-phosphonylmethoxyethyl) adenine (Gilead); PMPA:(R)-9-(2-phosphonylmethoxypropyl)-adenine (Gilead); Ro 31-8959:hydroxyethylamine derivative HIV-1 protease inhibitor (Roche); RPI-3121:peptidyl protease inhibitor, 1-[(3s)-3-(n-alpha-benzyloxycarbonyl)-1-asparginyl)-amino-2-hydroxy-4-phenylbutyryl]-n-tert-butyl-1-prolineamide; 2720:6-chloro-3,3-dimethyl-4-(isopropenyloxycarbonyl)-3,4-dihydro-quinoxalin-2(1H)thione; SC-52151: hydroxyethylurea isostere protease inhibitor(Searle); SC-55389A: hydroxyethyl-urea isostere protease inhibitor(Searle); TIBO R82150:(+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo-[4,5,1-jk]-[1,4]-benzodiazepin-2(1H)-thione (Janssen); TIBO 82913:(+)-(5S)-4,5,6,7-tetrahydro-9-chloro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1jk]-[1,4]-benzo-diazepin-2-(1H)-thione (Janssen);TSAO-m3T:[2′,5′-bis-O-(tert-butyldimethylsilyl)-3′-spiro-5′-(4′-amino-1′,2′-oxathiole-2′,2′-dioxide)]-β-D-pentofuranosyl-N-3-methyl-thymine;U90152:1-[3-[(1-methylethyl)-amino]2-pyridinyl]-4-[[5-[(methylsulphonyl)-amino]-1H-indol-2yl]-carbonyl]-piperazine;UC: thiocarboxanilide derivatives (Uniroyal);UC-781=N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furan-carbothioamide;UC-82=N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-thiophenecarbothioamide;VB 11,328: hydroxyethyl-sulphonamide protease inhibitor (Vertex);VX-478: amprenavir, 141W94, hydroxyethyl-sulphonamide protease inhibitor(Vertex/Glaxo Wellcome); XM 323: cyclic urea protease inhibitor (DupontMerck), famciclovir, gancyclovir and penciclovir. In another embodiment,the phenylindole is administered in combination with the proteaseinhibitor LG 1350.

[0446] In general, during alternation therapy, an effective dosage ofeach agent is administered serially, whereas in combination therapy,effective dosages of two or more agents are administered together. Thedosages will depend on such factors as absorption, biodistribution,metabolism and excretion rates for each drug as well as other factorsknown to those of skill in the art. It is to be noted that dosage valueswill also vary with the severity of the condition to be alleviated. Itis to be further understood that for any particular subject, specificdosage regimens and schedules should be adjusted over time according tothe individual need and the professional judgment of the persontadministering or supervising the administration of the compositions.Examples of suitable dosage ranges for anti-HIV compounds, includingnucleoside derivatives (e.g. D4T, DDI, and 3TC) or protease inhibitors,for example, nelfinavir and indinavir, can be found in the scientificliterature and in the Physicians Desk Reference. Many examples ofsuitable dosage ranges for other compounds described herein are alsofound in public literature or can be identified using known procedures.These dosage ranges can be modified as desired to achieve a desiredresult.

[0447] The disclosed combination and alternation regiments are useful inthe prevention and treatment of HIV infections and other relatedconditions such as AIDS-related complex (ARC), persistent generalizedlymphadenopathy (PGL), AIDS-related neurological conditions, anti-HIVantibody positive and HIV-positive conditions, Kaposi's sarcoma,thrombocytopenia purpurea and opportunistic infections. In addition,these compounds or formulations can be used prophylactically to preventor retard the progression of clinical illness in individuals who areanti-HIV antibody or HIV-antigen positive or who have been exposed toHIV.

[0448] V. Pharmaceutical Compositions

[0449] Humans suffering from effects caused by any of the diseasesdescribed herein, and in particular, HIV infection, can be treated byadministering to the patient an effective amount of the phenylindole,optionally in combination or alternation with another anti-HIV agent, orwith a pharmaceutically acceptable salt or prodrug thereof in thepresence of a pharmaceutically acceptable carrier or diluent. In oneembodiment, humans infected with HIV can be effectively treated byadministering to the patient an effective amount of the phenylindole ora pharmaceutically acceptable salt or prodrug thereof in the presence ofa pharmaceutically acceptable carrier or diluent. For multiple drugresistant patients, the phenylindole is either administered alone or incombination. The active materials can be administered by any appropriateroute, for example, orally, parenterally, enterally, intravenously,intradermally, subcutaneously, transdermally, intranasally or topically,in liquid or solid form.

[0450] The active compound(s) are included in the pharmaceuticallyacceptable carrier or diluent in an amount sufficient to deliver to apatient a therapeutically effective amount of compound to inhibit viralreplication in vivo, especially HIV replication, without causing serioustoxic effects in the treated patient. By “inhibitory amount” is meant anamount of active ingredient sufficient to exert an inhibitory effect asmeasured by, for example, an assay such as the ones described herein.

[0451] A preferred dose of the compound for all the above-mentionedconditions will be in the range from about 1 to 75 mg/kg, preferably 1to 20 mg/kg, of body weight per day, more generally 0.1 to about 100 mgper kilogram body weight of the recipient per day. The effective dosagerange of the pharmaceutically acceptable derivatives can be calculatedbased on the weight of the parent phenylindole to be delivered. If thederivative exhibits activity in itself, the effective dosage can beestimated as above using the weight of the derivative, or by other meansknown to those skilled in the art.

[0452] The compounds are conveniently administered in unit any suitabledosage form, including but not limited to one containing 7 to 3000 mg,preferably 70 to 1400 mg of active ingredient per unit dosage form. Anoral dosage of 50 to 1000 mg is usually convenient.

[0453] Ideally, the active ingredient should be administered to achievepeak plasma concentrations of the active compound of from about 0.02 to70 micromolar, preferably about 0.5 to 10 μM. This may be achieved, forexample, by the intravenous injection of a 0.1 to 25% solution of theactive ingredient, optionally in saline, or administered as a bolus ofthe active ingredient.

[0454] The concentration of active compound in the drug composition willdepend on absorption, distribution, metabolism and excretion rates ofthe drug as well as other factors known to those of skill in the art. Itis to be noted that dosage values will also vary with the severity ofthe condition to be alleviated. It is to be further understood that forany particular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed composition. The active ingredient may be administered atonce, or may be divided into a number of smaller doses to beadministered at varying intervals of time.

[0455] A preferred mode of administration of the active compound isoral. Oral compositions will generally include an inert diluent or anedible carrier. They may be enclosed in gelatin capsules or compressedinto tablets. For the purpose of oral therapeutic administration, theactive compound can be incorporated with excipients and used in the formof tablets, troches, or capsules. Pharmaceutically compatible bindagents, and/or adjuvant materials can be included as part of thecomposition.

[0456] The tablets, pills, capsules, troches and the like can containany of the following ingredients, or compounds of a similar nature: abinder such as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, Primogel, or corn starch; a lubricant such as magnesiumstearate or Sterotes; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate or orange flavoring. When the dosageunit form is a capsule, it can contain, in addition to material of theabove type, a liquid carrier such as a fatty oil. In addition, dosageunit forms can contain various other materials which modify the physicalform of the dosage unit, for example, coatings of sugar, shellac, orother enteric agents.

[0457] The compounds can be administered as a component of an elixir,suspension, syrup, wafer, chewing gum or the like. A syrup may contain,in addition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors.

[0458] The compounds or their pharmaceutically acceptable derivative orsalts thereof can also be mixed with other active materials that do notimpair the desired action, or with materials that supplement the desiredaction, such as antibiotics, antifungals, antiinflammatories, proteaseinhibitors, or other nucleoside or non-nucleoside antiviral agents, asdiscussed in more detail above. Solutions or suspensions used forparental, intradermal, subcutaneous, or topical application can includethe following components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. The parentalpreparation can be enclosed in ampoules, disposable syringes or multipledose vials made of glass or plastic.

[0459] If administered intravenously, preferred carriers arephysiological saline or phosphate buffered saline (PBS).

[0460] Liposomal suspensions (including liposomes targeted to infectedcells with monoclonal antibodies to viral antigens) are also preferredas pharmaceutically acceptable carriers. these may be prepared accordingto methods known to those skilled in the art, for example, as describedin U.S. Pat. No. 4,522,811 (which is incorporated herein by reference inits entirety). For example, liposome formulations may be prepared bydissolving appropriate lipid(s) (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidylcholine, and cholesterol) in an inorganic solvent that is thenevaporated, leaving behind a thin film of dried lipid on the surface ofthe container. An aqueous solution of the active compound or itsmonophosphate, diphosphate, and/or triphosphate derivatives is thenintroduced into the container. The container is then swirled by hand tofree lipid material from the sides of the container and to disperselipid aggregates, thereby forming the liposomal suspension.

[0461] VI. Process of Preparation of the Active Compounds

[0462] The phenylindoles can be synthesized using any means known in theart. In particular, the methods disclosed in U.S. Pat. No. 5,527,819,hereby incorporated by reference in its entirety for its disclosure ofrelevant synthetic methods, can be used to synthesize the compounds ofthe present invention. In general, the compounds of the presentinvention can be synthesized via the general methods disclosed in FIGS.1-4. In particular, the following species can by synthesized by thefollowing methods.

[0463] a) Ethyl indole-2-caboxylates-2a-i (Scheme 1, Examples 1-3)

[0464] Ethyl 5,6-dichloroindole-2-carboxylate 2a was prepared accordingto literature (J. Med. Chem., 1998, 41, 1568-1573). Ethylindole-2-caboxylates 2b-i were synthesized starting from proper anilinesor phenylhydrazines which were transformed into the relatedphenylhydrazones 1 and then cyclized to indoles (Fischer indolesynthesis, Robinson, “The Fischer indole synthesis”, Wiley, New York,1983. The Japp-Klingemann reaction, Org. Reactions, 1959, 10, 143-178).

[0465] b) 3-Arylsulfonylindole-2-carboxyamides-5a-g (Scheme 2, Examples4-7)

[0466] The reaction of ethyl indole-2-caboxylates 2a-i withN-(3,5-dimethylphenylthio)-succinimide in the presence of sodium hydrideafforded the ethyl 3-(3,5-dimethylphenylthio)indole-2-caboxylates 3a-iwhich were oxidized to the related sulfones 4a-i by treatment with3-chloroperoxybenzoic acid. Transformation of esters 3a-i into relatedamides 4a-i was reached by heating in a sealed tube with ammoniumhydroxide.

[0467] c) 3-Arylsulthioindole-2-carboxyhydrazides—6a-d, f and 7a-f—and3-aryl-sulfonylindole-2-carboxyhydrazides—8a, b, d-f, 9a-f, 10 and 11(Schemes 3 and 4, Examples 8-10)

[0468] Treatment of ethyl 3-aryllthioindole-2-caboxylates or3-arylsulfonylindole-2-caboxylates with proper hydrazines afforded3-arylsulthioindole-2-carboxyhydrazides (6a-d, f and 7a-f) and3-arylsulfonylindole-2-carboxyhydrazides (8a, b, d-f and 9a-f, 10),respectively. Reaction of 7e with acetone in the presence of sodiumcyanoborohydride gave 11.

[0469] d)1-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carbonyl]-4-methyl-piperazine-13(Scheme 5, Examples 11 and 12)

[0470] Lithium hydroxide hydrolysis of 41 gave5-chloro-3-(3,5-dimethylphenyl-sulfonyl)indole -2-carboxylic acid (12)with was converted to 13 by reaction with N-methylpiperazine in thepresence of benzotriazol-1-yl-oxy-tris(dimethylamino)-phosphoniumhexafluorophosphate (BOP reagent) and triethylamine in DMF as a solventat room temperature.

[0471] e)3-trans-15-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-yl]propenamide-18(Scheme 6, Examples 13-18)

[0472] Acid (12) was transformed into N-methyl,N-methoxy5-chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide (14) byreacting with N,O-dimethyl-hydroxylamine hydrochloride,benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluoro-phosphate(BOP reagent) in the presence of triethylamine and then into5-chloro-3-(3,5-di-methylphenylsulfonyl)indole-2-carboxyaldehyde acid(15) by lithium aluminium hydride reduction. Reaction of 15 withtriethyl phosphono acetate in the presence of potassium carbonate gaveethyl 3-trans-[5-chloro-3-(3,5-dimethylphenyl-sulfonyl)indol-2-yl]propenoate (16), which was transformed to3-trans-[5-chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-yl]propenoicacid (17) by lithium aluminium hydrolysis and subsequently converted toamide 18 with ammonia in the presence of 1,1′-carbonyldiimidazole.Reaction of acid 17 with the gyicine ethyl ester hydrochloride in thepresence of BOP and triethylamine afforded2-[N-[3-trans-[5-chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-yl]propenamido]]-aceticacid ethyl ester) (19) which was transformed into the related amide 20with ammonium hydroxide at 60° C.

[0473] f)2-[N-15-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carboxyamido]]-acetamide-21 (Scheme 7, Examples 19-22)

[0474] Reaction of the acid 12 with the glycine ethyl esterhydrochloride in the presence of BOP and triethylamine afforded2-N-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carboxy-amido]]-acetic acid ethyl ester (21) which was transformedinto amide 22 by heating with ammonium hydroxide. By the same way wereprepared amides 23 and 24 by heating with cyclopropylamine ormorpholine, respectively.

[0475] g)5-(1H-Pyrrol-1-yl)-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide-25b(Scheme 8, Example 23)

[0476] 5-Nitro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide (5k)was reduced 5-amino-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamidewith hydrogen in the presence of PtO₂ (Adams' catalyst) as a catalyst.Transformation into5-(1H-pyrrol-1-yl)-3-(3,5-dimethyl-phenylsulfonyl)indole-2-carboxylate(25a) was performed by heating with 2,5-dimethoxy-tetrahydrofuran inglacial acetic acid (Acta Chem. Scand., 1952, 6, 667-670; Acta Chem.Scand., 1952, 6, 867-874).

[0477] The following working examples provide a further understanding ofthe method of the present invention. These examples are of illustrativepurpose, and are not meant to limit the scope of the invention.Equivalent, similar, or suitable solvents, reagents or reactionconditions may be substituted for those particular solvents, reagents orreaction conditions described herein without departing from the generalscope of the method of synthesis.

EXAMPLES

[0478] All melting points (mp) were taken on a Buichi 510 apparatus(uncorrecte). Infrared spectra (1R): Perkin-Elmer 1310spectrophotometer. Proton nuclear magnetic resonance (1H NMR) spectra:Bruker AM-200 (200 MHz) FT spectrometer. Column chromatographies:alumina Merck (70-230 mesh) and silica gel Merck (70-230 mesh). TLC:Aluminum oxide TLC cards Fluka (aluminum oxide precoated aluminum cardswith fluorescent indicator at 254 nm) and silica gel TLC cards Fluka(silica gel precoated aluminum cards with fluorescent indicator at 254nm). Developed plates were visualized by spectroline ENF 260C/F UVapparatus. Organic solutions were dried over anhydrous sodium sulfate.Concentration and evaporation of the solvent after reaction orextraction: rotary evaporator Buchi Rotavapor operating at reducedpressure. Elemental analyses (t 0.4% of the theoretical values):laboratories of Dr. M. Zancato, Dipartimento di Scienze Farmaceutiche,University of Padova (Italy).

Example 1

[0479] Synthesis of Ethyl Pyruvate 4-Chloro-3-Fluorophenylhydrazone

[0480] A solution of sodium nitrite (4.76 g, 0.069 mol) in water (6.3mL) was added dropwise to an ice cooled mixture of4-chloro-3-fluoroaniline (J. Am. Chem. Soc., 1996, 61, 5130-5133) (10.00g, 0.069 mol), water (167 mL) and 37% hydrochloric acid (167 mL). After20 minutes potassium acetate (9.81 g, 0.10 mol) was added, and then asolution of ethyl 2-methylacetoacetate (9.95 g, 0.069 mol), potassiumacetate (9.81 g, 0.10 mol) in methanol (67 mL) was dropped while coolingon the ice bad. Reaction was stirred at 0° C. for 3 hours, thenextracted with diethyl ether. Organic layer was washed with brine anddried. Removal of the solvent furnished a red oily residue that wastreated with ethanol (100 mL) and stirred at room temperature overnight.The solid which formed was filtered a recrystallized from ethanol togive 5.4 g (30%) of title compound, mp 161-163° C. (from ethanol).

[0481] Ethyl pyruvate 2,4-difluorophenylhydrazone, yield 40%, mp153-156° C. (from ethanol).

[0482] Ethyl pyruvate 3-chloro-4-fluorophenylhydrazone, yield 17%, mp89-91° C. (from aqueous ethanol).

[0483] Ethyl pyruvate 3,4-difluorophenylhydrazone, yield 53%, mp 112-114(from ethanol).

Example 2

[0484] Synthesis of Ethyl pyruvate 2,4-dichlorophenylhydrazone

[0485] A mixture of 2,4-dichlorophenylhydrazine (16.00 g, 0.075 mol),ethyl pyruvate (14.47 g, 10.3 mL, 0.12 mol), glacial acetic acid (0.9mL), absolute ethanol (105 mL) was refluxed for 2 hours. After coolingat room temperature, the solid which formed was filtered andrecrystallized from ethanol to give 17.0 g (83%) of the title compound,mp 118-120° C. (from ethanol).

Example 3

[0486] Synthesis of Ethyl 5-chloro-6-fluoroindole-2-carboxylate (2f) andethyl 5-chloro-4-fluoroindole-2-carboxylate (2 g)

[0487] Ethyl pyruvate 4-chloro-3-fluorophenylhydrazone (5.00 g, 0.0193mol) was added by portions to PPA (50 g) pre-heated at 110° C., thenreaction was stirred for 30 minutes. After cooling at room temperature,ice water was added while stiirning. The solid which formed wasfiltered, washed with water, dried and passed by a silica gel columnchromatography (n-hexane:ethyl acetate 1:2 as eluent). First fractionsfurnished ethyl 5-chloro-6-fluoroindole-2-carboxylate (2f), (1.85 g,40%), mp 160-164° C. (ethanol). Further elution with the same eluentgave ethyl 5-chloro-4-fluoroindole-2-carboxylate (2 g) (0.9 g, 19%), mp186-190° C. (ethanol).

[0488] Ethyl 5,7-dichloroindole-2-carboxylate (2b), yield 37%, mp143-145° C. (from ethanol).

[0489] Ethyl 4,5-difluoroindole-2-carboxylate (2c), yield 15%, mp166-168° C. (from ethanol).

[0490] Ethyl 4,5-difluoroindole-2-carboxylate (2d), yield 22%, mp171-173° C. (from ethanol.)

[0491] Ethyl 5,7-difluoroindole-2-carboxylate (2e), yield 9%, mp175-177° C. (from ethanol).

[0492] Ethyl 4-chloro-5-fluoroindole-2-carboxylate (2 h), yield 18%, mp183-16° C. (from ethanol).

[0493] Ethyl 6-chloro-5-fluoroindole-2-carboxylate (2i), yield 61%, mp198-200° C. (from ethanol).

Example 4

[0494] Synthesis of Ethyl5-chloro-3-(3,5-dimethylphenylthio)-6-fluoroindole-2-carboxylate (3f)

[0495] Boron trifluoride ethyl etherate (0.135 g, 0.12 mL, 0.001 mol)was added to a mixture of ethyl 5-chloro-6-fluoroindole-2-carboxylate(0.75 g, 0.0031 mol), N-(3,5-dimethylphenylthio)-succinimide (0.78 g,0.0033 mol) and anhydrous dichloromethane (20 mL) under dry argonatmosphere. After stirring at room temperature for 2 hours was addedboron trifluoride ethyl etherate (0.27 g, 0.24 mL, 0.002 mol) and thenreaction was heated at 45° C. for 2 hours. After cooling reaction wasdiluted chloroform and brine while shaking. Organic layer was separated,washed with saturated solution of sodium hydrogen carbonate, then withbrine and dried. The solvent was evaporated to give 1.2 g (100%) ofsatisfactory pure title compound, mp 170-173° C. (from ethanol).

[0496] Ethyl 5,6-dichloro-3-(3,5-dimethylphenylthio)indole-2-carboxylate(3a), yield 96%, mp 192-195° C. (from ethanol).

[0497] Ethyl 5,7-dichloro-3-(3,5-dimethylphenylthio)indole-2-carboxylate(3b), not purified.

[0498] Ethyl 3-(3,5-dimethylphenylthio)-4,5-difluoroindole-2-carboxylate(3c), yield 97%, mp 148-150° C. (from ethanol).

[0499] Ethyl 3-(3,5-dimethylphenylthio)-5.6-difluoroindole-2-carboxylate(3d), yield 98%, mp 171-174° C. (from ethanol).

[0500] Ethyl 3-(3,5-dimethylphenylthio)-5,7-difluoroindole-2-carboxylate(3e), not purified.

[0501] Ethyl5-chloro-3-(3,5-dimethylphenylthio)-4-fluoroindole-2-carboxylate (3g),yield 51%, mp 149-151° C. (from ethanol).

[0502] Ethyl4-chloro-3-(3,5-dimethylphenylthio)-5-fluoroindole-2-carboxylate (3h),yield 77%, mp 184-186° C. (from ethanol).

[0503] Ethyl6-chloro-3-(3,5-dimethylphenylthio)-5-fluoroindole-2-carboxylate (3i),yield 61%, mp 186-190° C. (from ethanol).

[0504] Methyl 5-chloro-3-(3,5-dimethylphenylthio)indole-2-carboxylate(3j), yield 77%, mp 174-175° C. (from toluene/cyclohexane).

[0505] Ethyl 5-nitro-3-(3,5-dimethylphenylthio)indole-2-carboxylate(3k), yield 46%, mp 212-213° C. (from ethanol).

[0506] Ethyl 5-acetyl-3-(3,5-dimethylphenylthio)indole-2-carboxylate(3l), yield 70%, mp 164-166° C. (from ethanol).

Example 5

[0507] Synthesis of Ethyl5-chloro-3-(3,5-dimethylphenysulfonyl)-6-fluoroindole-2-carboxylate (4f)

[0508] 3-Chloroperoxybenzoic acid (1.32 g, 0.00766 mol) was added to anice cooled solution of ethyl5-chloro-3-(3,5-dimethylphenylthio)-6-fluoroindole-2-carboxylate (3f)(1.0 g, 0.00264 mol) in chloroform (42 mL). Reaction was stirred at roomtemperature for 1.5 hours, poured on crushed ice and extracted withchloroform. Organic solution was shaken with saturated solution ofsodium hydrogen carbonate, then with brine. After concentration to asmall volume, the solution was passed through a silica gel columnchromatography (ethyl acetate as eluent) to furmish 0.9 g (83%) of titlecompound, mp 236-240° C. (from ethanol).

[0509] Ethyl5,6-dichloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxylate (4a),yield 82%, mp 196-197° C. (from aqueous ethanol).

[0510] Ethyl5,7-dichloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxylate (4b),yield 50%.

[0511] Ethyl3-(3,5-dimethylphenylsulfonyl)-4,5-difluoroindole-2-carboxylate (4c),yield 27%, mp 176-178° C. (from ethanol).

[0512] Ethyl3-(3,5-dimethylphenylsulfonyl)-5.6-difluoroindole-2-carboxylate (4d),yield 100%, mp 232-235° C. (from ethanol).

[0513] Ethyl3-(3,5-dimethylphenylsulfonyl)-5.7-difluoroindole-2-carboxylate (4e),yield 100%, mp 208-210° C. (from ethanol).

[0514] Ethyl5-chloro-3-(3,5-dimethylphenylsulfonyl)-4-fluoroindole-2-carboxylate (4g), yield 89%, mp 224-226° C. (from ethanol).

[0515] Ethyl4-chloro-3-(3,5-dimethylphenylsulfonyl)-5-fluoroindole-2-carboxylate(4h), yield 54%, mp 232-234° C. (from ethanol).

[0516] Ethyl6-chloro-3-(3,5-dimethylphenylsulfonyl)-5-fluoroindole-2-carboxylate(4i), yield 100%, mp 233-235° C. (from ethanol).

[0517] Methyl5-chloro-3-(3,5-dimethylphenylsulfonyl)-indole-2-carboxylate (4j), yield74%, mp 234-236° C. (from toluene/cyclohexane).

[0518] Ethyl 5-nitro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxylate(4k), yield 100%, mp 255-256° C. (from ethanol).

[0519] Ethyl 5-acetyl-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxylate(41), yield 61%, mp 193-195° C. (from ethanol).

Example 6

[0520] Synthesis of5-Chloro-3-(3,5-dimethylphenysulfonyl)-6fluoroindole-2-carboxyamide (5f)

[0521] Ethyl5-chloro-3-(3,5-dirnethylphenysulfonyl)-6fluoroindole-2-carboxylate (41)was heated with 30% ammoniumn hydroxide (25 mL) and ammonium chloride(40 mg) in a sealed tube at 100° C. overnight. After cooling reactionmixture was poured on ice water and stirred for 15 minutes and extractedwith ethyl acetate. Organic layer was washed with brine, dried and thesolvent evaporated to afford a residue which was purified on silica gelcolumn chromatography (chloroform-ethanol 95:5). Removal of the solventgave 0.28 g (65%) of title compound, mp 270-270° C. (from ethanol).

[0522] 5,6-Dichloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide(5a), yield 43%, mp 280-282° C. (from ethanol).

[0523] 5,7-Dichloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide(5b), yield 90%, mp >300° C. (from ethanol).

[0524] 3-(3,5-Dimethylphenylsulfonyl)-4,5-difluoroindole-2-carboxyamide(5c), yield 43%, mp 298-300° C. (from ethanol).

[0525] 3-(3,5-Dimethylphenylsulfonyl)-5.6-difluoroindole-2-carboxyamide(5d), yield 65%, mp 266-269° C. (from aqueous dimethylformamide).

[0526] 3-(3,5-Dimethylphenylsulfonyl)-5.7-difluoroindole-2-carboxyamide(5e), yield 75%, mp >300° C. (from aqueous dimethylformamide).

[0527]5-Chloro-3-(3,5-dimethylphenylsulfonyl)-4-fluoroindole-2-carboxyamide(5g), yield 31%, mp 268-270° C. (from ethanol).

[0528]4-Chloro-3-(3,5-dimethylphenylsulfonyl)-5-fluoroindole-2-carboxyamide(5h), yield 46%, mp 279-280° C. (from ethanol).

[0529]6-Chloro-3-(3,5-dimethylphenylsulfonyl)-5-fluoroindole-2-carboxyamide(5i), yield 50%, mp 262-264° C. (from ethanol).

[0530] 5-Chloro-3-(3,5-dimethylphenylsulfonyl)-indole-2-carboxyamide(5j), yield 64%, mp 280-284° C. (from ethanol).

[0531] 5-Nitro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide (5k),yield 57%, mp 270-272° C. (from ethanol).

[0532] 5-Acetyl-3-(3,5-dimethylphenylthio)indole-2-carboxyamide (5l),yield 54%, mp>300° C. (from ethanol).

Example 7

[0533] Synthesis ofN-(3,5-Dimethylphenylthio)succinimide

[0534] 3,5-Dimethylthiophenol (2.76 g, 0.02 mol) was added by a syringeto an ice cooled mixture of N-chlorosuccinimide (3.34 g, 0.025 mol) andanhydrous dichloromethane (30 mL) under argon atmosphere. After 1 hour,N-chlorosuccinimide (0.4 g, 0.003 mol) was added, then reaction wasstirred for 2.5 hours. Triethylamine (3.9 mL, 0.028 mol) was added whilestirring for 15 minutes, then dichloromethane and 1N HCl were added.After shaking, organic layer was dried, concentrated to a small volumeand passed through a Celite® column. After evaporation of the solvent,the residue was triturated with diethyl ether to give 3.0 g (64%) oftitle compound, mp 131-134° C. (from diethyl ether).

Example 8

[0535] Synthesis of5-Chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxy-hydrazide (7e)

[0536] A mixture of ethyl5-chloro-3-(3,5-dimethylphenylsulfonyl)-indole-2-carboxylate (1.00 g,0.0026 mol), hydrazine hydrate (5 mL) and ethanol (5 mL) was stirred atroom temperature for 2 hours. After quenching on crushed ice, the solidwhich formed was filtered, washed with water and dried to give 0.77(82%) of title compound, mp>300° C. (from aqueous dimethylformamide).

[0537] 5-Chloro-3-phenylthioindole-2-carboxyhydrazide (6a), yield 80%,mp 231° C. (from ethanol).

[0538] 5-Chloro-3-(4-methylphenylthio)indole-2-carboxyhydrazide (6b),yield 90%, mp 249-250° C. (from ethanol).

[0539] 5-Chloro-3-(4-fluoromethylphenylthio)indole-2-carboxyhydrazide(6c), yield 90%, mp 235-236° C. (from ethanol).

[0540] 5-Chloro-3-(4-chlorophenylthio)indole-2-carboxyhydrazide (6d),yield 100%, mp 247-248° C. (from ethanol).

[0541] 5-Chloro-3-phenylsulfonylindole-2-carboxyhydrazide (7a), yield100%, mp>300° C. (from ethanol).

[0542] 5-Chloro-3-(4-methyhlphenylsulfonyl)indole-2-carboxyhydrazide(7b), yield 100%, mp>300° C. (from ethanol).

[0543] 5-Chloro-3-(4-fluorophenylsulfonyl)indole-2-carboxyhydrazide(7c), yield 55%, mp 252-253° C. (from ethanol).

[0544] 5-Chloro-3-(4-chlorophenylsulfonyl)indole-2-carboxyhydrazide(7d), yield 90%, mp>300° C. (from ethanol).

Example 9

[0545] Synthesis of5-Chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-[N′-(2-hydroxy-ethyl)]-carboxyhydrazide(9f)

[0546] A mixture of ethyl5-chloro-3-(3,5-dimethylphenylsulfonyl)-indole-2-carboxylate (1.00 g,0.0026 mol), 2-hydroxyethylhydrazine (5 mL) and ethanol (5 mL) wasstirred at room temperature overnight. After quenching on crushed ice,the solid which formed was filtered, washed with water and dried to give0.95 (90%) of title compound, mp 228-230° C. (from ethanol).

[0547]5-Chloro-3-phenylthioindole-2-[N′-(2-hydroxyethyl)]carboxyhydrazide(8a), yield 88%, mp 178-180° C. (from ethanol).

[0548]5-Chloro-3-(2-methylphenylthio)indole-2-[N′-(2-hydroxyethyl)]carboxyhydrazide(8b), yield 70%, mp 190-192° C. (from ethanol).

[0549]5-Chloro-3-(4-methylphenylthio)indole-2-[N′-(2-hydroxyethyl)jcarboxyhydrazide(8d), yield 65%, mp 211-213° C. (from aqueous ethanol).

[0550]5-Chloro-3-(2,4-dimethylphenylthio)indole-2-[N′-(2-hydroxyethyl)lcarboxyhydrazide(8e), yield 59%, mp 170-172° C. (from toluene/cyclohexane).

[0551]5-Chloro-3-(3,5-dimethylphenylthio)indole-2-[N′-(2-hydroxyethyl)]carboxyhydrazide(8f), yield 52%, mp 215-217° C. (from ethanol).

[0552]5-Chloro-3-phenylsulfonylindole-2-[N′-(2-hydroxyethyl)]carboxyhydrazide(9a), yield 88%, mp 178-180° C. (from ethanol).

[0553]5-Chloro-3-(2-methylphenylsulfonyl)indole-2-[N′-(2-hydroxyethyl)lcarboxyhydrazide(9b), yield 83%, mp 220-221° C. (from ethanol).

[0554]5-Chloro-3-(3-methylphenylsulfonyl)indole-2-[N′-(2-hydroxyethyl)]carboxyhydrazide(9c), yield 98%, mp 210-215° C. (from ethanol).

[0555]5-Chloro-3-(4-methylphenylsulfonyl)indole-2-[N′-(2-hydroxyethyl)lcarboxyhydrazide(9d), yield 84%, mp 281-283° C. (from ethanol).

[0556]5-Chloro-3-(2,4-dimethylphenylsulfonyl)indole-2-[N′-(2-hydroxyethyl)]carboxyhydrazide(9e), yield 94%, mp 141-143° C. (from ethanol).

[0557]5-Chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-(N′-methyl)carboxyhydrazide(10), yield 16%, mp 284-287° C. (aqueous dimethylformamide).

Example 10

[0558] Synthesis of5-Chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-(N′-isopropyl)-carboxy-hydrazide(11)

[0559] Sodium cyanoborohydride (0.19 g, 0.0031 mol) was added to an icecooled solution of5-chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyhydrazide (7e)(0.98 g, 0.0026 mol), acetone (0.15 g, 0.0026 mol), tetrahydrofuran(32.5 mL) and methanol (32.5 mL) containing 6N HCl—CH₃OH 1:1 (0.44 mL).Reaction was stirred at 0° C. for 2 hours, then at room temperatureovernight. After concentration to a small volume, water and ethylacetate were added while shaking. Organic layer was separated, washedwith brine and dried. Removal of the solvent gave a residue which waspurified by passing through a silica gel column chromatography(chloroform-ethanol 95:5 as eluent) to afford 0.68 g (63%) of titlecompound, mp 248-250° C. (from ethanol).

Example 11

[0560] Synthesis of5-Chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxylic acid (12)

[0561] Lithium hydroxide monohydrate (0.33 g, 0.0079 mol) was added to asolution of methyl5-chloro-3-(3,5-dimethylphenylthio)indole-2-carboxylate (1.0 g, 0.0026mol) in tetrahydrofuran (30 mL) and water (30 mL), then reaction wasstirred at room temperature for 4 days. After dilution with water themixture was acidified with 1N HCl and extracted with ethyl acetate.Organic reaction was washed with brine and dried. Evaporation of thesolvent furmished 0.94 (100%) of title compound, mp 277-278° C. (fromethanol).

Example 12

[0562] Synthesis of1-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carbonyl]-4-methyl-piperazine(13)

[0563] Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP reagent) (1.22 g, 0.00275 g) was added to asolution of 5-chloro-3-(3,5-dimethylphenyl-sulfonyl)indole-2-carboxylicacid (12) (1.00 g, 0.00275 mol), N-methylpiperazine (0.55 g, 0.0055mol), triethylamine (0.55 g, 0.0055 mol) in anhydrous DMF (50 mL).Reaction was stirred at room temperature for 72 hours, then diluted withwater and extracted with ethyl acetate. Organic extracts were washedwith brine, dried and the solvent evaporated to give 1.20 g (98%) ofpure title compound, mp 281-283° C. (from aqueous ethanol).N-Methyl,N-methoxy5-chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carboxyamide (14), wasprepared using N,O-dimethylhydroxylamine hydrochloride. Yield 70%, mp264-267° C. (ethanol).

Example 13

[0564] Synthesis of5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carboxy-aldehyde (15)

[0565] A 1M solution of lithium aluminium hydride (1.6 mL, 0.0015 mol)was slowly added via syringe to a solution of 14 (0.6 g, 0.0015 mol) inanhydrous tetrahydrofuran (40 mL) under argon atmosphere. Reaction wasstirred at room temperature for 1.5 hours, then quenched by carefullyaddition of crushed ice. The solid that formed was filtered, washed withtetrahydrofuran and concentrated to a small volume. After extractionwith ethyl acetate, the organic layer was washed with brine and dried.Removal of the solvent furnished 0.5 g (96%) of satisfactory pure titlecompound, mp 253-255° C. (from aqueous ethanol).

Example 14

[0566] Synthesis of Ethyl3-trans-[5-chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-yl]propionate(16)

[0567] Triethyl phosphonoacetate (0.36 g, 0.016 mol) was added in oneportion to a mixture of 15 (0.45 g, 0.0013 mol), potassium carbonate(0.53 g, 0.0039 mol) and absolute ethanol (10 mL), then reaction wasstirred at 70° C. per 2 hours. After cooling water and diethyl etherwere added while shaking. The organic layer was separated, washed withbrine and dried. After evaporation of the solvent, the crude product waspurified by passing through a silica gel column chromatography (ethylacetate as eluent) to give 0.27 g (50%) of pure title compound, mp236-238° C. (from ethanol).

Example 15

[0568] Synthesis of3-trans-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-yl]-propionicacid (17)

[0569] Was prepared by lithium hydroxide hydrolysis of 16, as reportedabove for acid 12. After 48 hours was obtained satisfactory pure titlecompound, yield 89%, mp 155-156° C. (from aqueous ethanol).

Example 16

[0570] Synthesis of3-trans-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-yl]-propionamide(18)

[0571] 1,1′-Carbonyldiimidazole (0.24 g, 0.0015 mol) was added byportions to an ice water cooled solution of 17 in anhydroustetrahydrofuran. Reaction was stirred at room temperature for 2 hours,then gaseous ammonia was bubbled through for 30 minutes. After dilutionwith water, the mixture was extracted with ethyl acetate, washed withbrine and dried. Removal of the solvent gave a residue, which waspurified by passing through a silica gel column chromatography (ethylacetate/ethanol 9:1 as eluent). Evaporation of the eluent gave 0.19 g(51%) of title compound, mp>300° C. (from aqueous dimethylformamide).

Example 17

[0572] Synthesis of2-[N-[3-trans-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-yl]propion-amido]]-aceticAcid Ethyl Ester (19)

[0573] Benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP reagent) (0.90 g, 0.0020 mol) was added to asolution of3-trans-[5-chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-yl]propionicacid (17) (0.80 g, 0.0020 mol), glycine ethyl ester hydrochloride (0.57g, 0.0041 mol) and triethylamine (0.62 g, 0.0061 mol) in anhydrous DMF(37 mL). Reaction was stirred at room temperature for 48 hours, thendiluted with water and extracted with ethyl acetate. Organic layer wasseparated, washed with brine and dried. Removal of the solvent furnished0.8 g (82%) of satisfactory pure title compound, mp 278-280° C. (fromethanol).

[0574]2-[N-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carboxy-amido]]aceticacid ethyl ester (21), was prepared from5-chloro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxylic acid(12)-after 72 hours at room temperature the reaction mixture was dilutedwith water; the solid which formed was filtered, washed with water anddried to give 0.62 g (80%) of satisfactory pure title compound, mp209-211° C. (from ethanol).

Example 18

[0575] Synthesis of2-[N-[3-trans-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-yl]propion-amido]]-acetamide(20)

[0576] A suspension of 19 (0.30 g, 0.0006 mol), in ethanol (28 mL) and30% anmnonium hydroxide (17 mL) was stirred at 60° C. for 1.5 hours.After cooling the mixture was diluted with water and extracted withethyl acetate. Organic layer was separated, washed with brine and dried.Removal of the solvent furnished 0.2 g (65%) of pure title compound,mp>300° C. (from ethanol).

[0577]2-[N-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carboxy-amido]]-acetamide(22), was prepared from2-[N-[5-chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carboxyamido]]-aceticacid ethyl ester (21)- the crude product was passed through a silica gelcolumn chromatography (ethyl acetate), yield 95%, mp 265-267° C.(aqueous dimethylformamide).

Example 19

[0578] Synthesis of N-Cyclopropyl2-[N-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)-indol-2-carboxyamido]]acetamide(23)

[0579] A mixture of2-[N-[5-chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carboxy-amido]]-aceticacid ethyl ester (21), ethanol (5 mL) and cyclopropylamine (5 mL) washeated at 60° C. for 6hours. After concentration to a small volume, theresidue was extracted with ethyl acetate, washed with brine and dried.Removal of the solvent furnished a crude product which was purified bypassing through a silica gel column chromatography (ethyl acetate) togive 0.14 g (69%) of title compound, mp 267-270° C. (ethanol).

[0580]N-(1-Morpholin-4-yl)-2-[N-[5-Chloro-3-(3,5-dimethylphenylsulfonyl)indol-2-carboxy-amido]]-acetamide(24), was prepared using morpholine—after 48 hours at 60° C., yield 74%,mp>300° C. (ethanol).

Example 20

[0581] Synthesis of5-(1H-Pyrrol-1-yl)-3-(3,5-dimethylphenylsuifonyl)indole-2-carboxyamide(25b)

[0582] A solution of5-nitro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide (5k) (0.25g, 0.0007 mol) in tetrahydrofuran (40 ML) and methanol (16 mL) wasreduced under an atmospheric pressure of hydrogen in the presence ofPtO₂ (50 mg) as a catalyst for 6 hours. Catalyst was separated byfiltration and the solvent evaporated to give 0.227 g (100%) of pure5-amino-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide as a brownoil. A solution of the last compound (0.227 g, 0.0007 mol),2,5-dimethoxythetrahydrofuran (0.09 g, 0.0006 mol) in glacial aceticacid (5 mL) was refluxed for 30 minutes. After evaporation of thesolvent the residue was triturated with ice water and extracted withethyl acetate. Organic layer was washed with brine and dried. Removal ofthe solvent left the crude product which was purified by passing througha silica gel column chromatography (ethyl acetate as eluent) to give0.15 g (57%) of title compound, mp 270-272° C. (from ethanol).

[0583] 5-(1H-Pyrrol-1-yl)-3-(phenylsulfonyl)indole-2-carboxyamide (25a),was prepared from 5-nitro-3-(phenylsulfonyl)indole-2-carboxyamide, yield71%, mp 250° C. (ethanol).

Example 21

[0584] Synthesis of5-(1-Hydroxyethyl)-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide(26)

[0585] Sodium borohydride (0.03 g, 0.0008 mol) was added to a mixture of5-acetyl-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide (51) (0.30g, 0.0008 mol) in tetrahydrofuran (8.5 mL) containing 0.1 mL of water,then reaction was refluxed for 1 hour. After cooling, water was addedwhile stirring for a few minutes, then the mixture was extracted withethyl acetate, washed with brine and dried. Removal of the solventfurnished 0.25 g (83%) of satisfactory pure title compound, mp 260-260°C. (ethanol).

Example 22

[0586] Preparation of 4,5-difluoro-3-(3,5-dimethylphenylsulphonyl)indole-2-carboxyserinamide

[0587] 4,5-Difluoro-3-(3,5-dimethylphenylsulphonyl)indole 2-carboxylicacid (3.52 g) and L-serinamide hydrochloride (2.77 g) were dissolved inanhydrous dimethylformamide (90 ml). Triethylamine (2.8 ml) was addedand the mixture stirred for 5 min.Benzotriazol-1-yloxy-tris(dimethylamino)phosphosphoniumhexafluorophosphate (BOP) (4.69 g) was added and the orange mixture wasstirred overnight at room temperature. The reaction mixture was dilutedwith water (350 ml) and the white solid precipitate collected byfiltration, washed with water and dried to afford the title product(3.86 g) as a white powder (97.9% pure by hplc).

[0588] In a similar manner5-chloro-4-fluoro-3-(3,5-dimethylphenylsulphonyl)indole-2-carboxyserinamide was prepared from the5-chloro-4-fluoro-3-(3,5-dimethylphenylsulphonyl) indole-2-carboxylicacid. The product was obtained as a white solid.

Example 23

[0589] Preparation of 4,5-difluoro-3-(3,5-dimethylphenylsulphonyl)indole-2-(2-(1-pyrrolo)ethyl)carboxamide

[0590] 4,5-difluoro-3-(3,5-dimethylphenylsulphonyl)indole 2-carboxylicacid (4.22 g) and 2-(1-pyrrolo)ethylamine (2.63 g) were dissolved inanhydrous dimethylformamide under an atmosphere of nitrogen (100 ml) andtriethylamine (3.2 ml) was added.Benzotriazol-1-yloxy-tris(dimethylamino)phosphosphoniumhexafluorophosphate (BOP)(5.63 g) was added and the yellow solution wasstirred at room temperature for 18 hours. The reaction mixture wasdiluted with water (350 ml) and stirred for 30 min. The whiteprecipitate was collected by filtration, washed with water and dried toafford the title product (5.18 g) as a white powder (97.1% pure byhplc).

[0591] In a similar manner5-chloro-4-fluoro-3-(3,5-dimethylphenylsulphonyl)indole-2-(2-(1-pyrrolo)ethyl)carboxamide was prepared from the5-chloro-4-fluoro-3-(3,5-dimethylphenylsulphonyl) indole-2-carboxylicacid. The product was obtained as a white solid.

Example 24

[0592] Preparation of 4,5-difluoro-3-(3,5-dimethylphenylsulphonyl)indole-2-(1-morpholinomethyl)carboxamide

[0593] 4,5-difluoro-3-(3,5-dimethylphenylsulphonyl)indole 2-carboxamide(670 mg) was mixed with 1,4-dioxan (18 ml) and the resultant whiteslurry was heated to reflux temperature. Morpholine (0.8 ml) and 37%aqueous formaldehyde (0.7 ml) were added and the mixture rapidly becamehomogeneous and was refluxed for 24 hours then allowed to cool andpoured into water (75 ml). The white slurry was stirred at roomtemperature for 4 hrs and the white solid was collected by filtration,washed with water and dried to afford the title product (730 mg) as awhite powder.

[0594] In similar fashion5-chloro-4-fluoro-3-(3,5-dimethylphenylsulphonyl)indole-2-(1-morpholinomethyl)carboxamide was prepared from5-chloro-4-fluoro-3-(3,5-dimethylphenylsulphonyl)indole 2-carboxamide.The product was obtained as a white solid.

[0595] VII. Biological Activity Against Drug Resistant Strains of HIV

[0596] In one embodiment the phenylindoles of the present invention donot exhibit significant cross resistance with other non-nucleosidesreverse transcriptase inhibitors (NNRTI), in that it displays an EC₅₀(in molar concentrations) in a mutant HIV strain of less thanapproximately 50, 25, 10 or 1 micromolar concentration. In a preferredembodiment, the non-nucleosides reverse transcriptase inhibitors (NNRTI)displays an EC₅₀ (in molar concentrations) in a mutant HIV strain ofless than approximately 5, 2.5, 1 or 0.1 micromolar concentration. Thedegree of cross-resistance against a drug resistant strain of HIV caneasily be measured by assessing the EC₅₀ of the desired indole in thetarget mutated i.e., drug resistant, virus.

[0597] Therefore, in another important embodiment of this invention, amethod for treating a patient with a cross-resistant HIV is providedthat includes administering an effective HIV-treatment amount of aphenylindole or its prodrug or salt.

Example 25

[0598] Influence ofPhenyl Substitution and Amido Group on Protein

[0599] Binding in presence of Glycoprotein or Human Serum Albumin

[0600] In order to understand how variations in the substituents on thephenyl ring, and variations at the 2-position of the indole ring, inthis class of compounds influence protein binding, a number ofrepresentative phenylindoles were tested in the presence of glycoproteinor human serum albumin, and compared to the prototype NNRTIs efavirenzand nevirapine. The structure of the tested compound is given below, andthe test results presented in Tables 1 and 2.

TABLE 1 EC₉₀ (Nx)^(d) Substituents α-GP^(b) HSA^(c) Cmpd. R R₁ RPMI^(a)1 mg/mL 45 mg/mL  1* H NH₂ 0.001 0.002 (2x) 0.01 (10x) 2 3,5 NH₂ 0.005 0.01 (2x)  0.2 (40x) diMe 3 3,5 NHNHC₂H₅OH 0.004  0.03 (7x) 0.27 (67x)diMe 4 3,5 NHCH₂CONH₂ 0.06  0.2 (3x)  4.8 (80x) diMe EFV 0.01  0.02 (2x)0.13 (13x)

[0601] TABLE 2 Compd. Substituents WT_(IIIB) K103R Y181C K103N-Y181C(CC₅₀)^(a) R R₁ EC₅₀ ^(b) EC₉₀ EC₉₀ ^(d) EC₅₀ EC₅₀ 4 (30) 3,5 diMeNHCH₂CO- 0.006 0.01 0.1 (10) 0.03 (5) 0.8 (133)  NH₂ 5 3,5 diMe NHCH₂CO-0.01 0.03   1 (33) 0.05 (5)  2 (200) (≧200) NHNH₂ 6 3,5 diMe CH═CHCO-0.06 0.03 >100 0.6 (10) >100 (1666)    (>200) NH₂ 7 (71) 3,5 diMeNHCH₂CH₂- 0.01 0.07 7 (100) 0.7 (70) 10 (1000) (2NO₂,5Me imidazole) NVP0.37 >30 >30 (200) EFV 0.004 0.008 1.8 0.025 0.15 (38)   (35)   (225)    (6)

Example 26

[0602] Influence of Substituents on the Indole Nucleus

[0603] Example 26 illustrates the influence of substituents at positions4, 5, 6, and 7 of the indole ring, in which position 2 of the indolering is maintained constant, and the substitution at the 3,5-position ofthe phenyl ring is either hydrogen or held constant with a 3,5-dimethylsubstitution. Table 3 presents the influence of these variations on theability of the compounds to protect cells from HIV-1 inducedpathogenecity. Comparisons are again made to nevirapine and efavirenz.

TABLE 3 Compd Substituents WT_(IIIB) K103R Y181C K103N-Y181C (CC₅₀)^(a)R R₁ EC₅₀ ^(b) EC₉₀ EC₉₀ ^(d) EC₅₀ EC₅₀ 8 (123) H 5,6 Cl 0.14 0.17 16(94) 2.6 (18) >100 (>714)  9 (19) 3,5 5,6 Cl 0.03 0.07 0.3 (4) 1.7(57) >100 (>3333) Me 10 (>200) 3,5 5,7 Cl 1.6 1.2 >100 >100 >100 (>62.5)Me (>83) 11 (17) 3,5 4,5 F 0.02 0.7 (35) >200 Me 12 ( ) 3,5 5,6 F ≦0.0030.07 (≧23.3) 2.6 (≧866) Me 13 (>200) 3,5 5,7 F 0.01 0.02 >100 2(200) >100 (>10000) Me (>5000) NVP (200) 0.37 >30 >30 EFV (35) 0.0040.008 1.8 (225) 0.025 (6) 0.15 (38)

[0604] This invention has been described with reference to its preferredembodiments. Variations and modifications of the invention, will beobvious to those skilled in the art from the foregoing detaileddescription of the invention. It is intended that all of thesevariations and modifications be included within the scope of thisinvention.

We claim:
 1. A compound of the formula (I):

or its pharmaceutically acceptable salt thereof, wherein (a) R¹ ishydrogen; acyl; —C(═O)H; —C(═W)H; —C(═O)R²; —C(═W)R²; —C(═O)OH;—C(═W)OH; —C(═O)OR²; —C(═W)OR²; —C(═O)SH; —C(=)W)SH; —C(═O)SR²;—C(═W)SR²; —C(═O)NH₂; —C(═W)NH₂; —C(═O)NHR²; —C(═W)NHR²; —C(═O)NR²R³;—C(═W)NR²R³; —C(═W)NH—(CH₂)_(p)-(amino acid) or —(CH₂)_(p)-(amino acid);(b) R^(4′), R^(5′), R^(6′), R^(7′), R^(2″), R^(3″), R^(4″), R^(5″) andR^(6″) are each independently H; halo (F, Cl, Br or I); —NO₂; —CN; —OH;—OR²; —SH; —SR²; —NH₂; —NHR²; —NR²R³; —NHSO₂—C₁₋₃alkyl;—NR²SO₂—C₁₋₃alkyl; —NHCO—C₁₋₃alkyl; —NR²CO—C₁₋₃alkyl; optionallysubstituted or unsubstituted branched or unbranched alkyl, alkenyl oralkynyl (such as an optionally substituted or unsubstituted branched orunbranched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, and in particular CH₃,CF₃, vinyl bromide, —CR²R²—S(O)_(n)—R³, —CR²R²NH₂, —CR²R²NHR²,—CR²R²NR²R³ and —CR²R²—C(═O)R²); alkacyl; optionally substituted orunsubstituted acyl; —C(═O)H; —C(═W)H; —C(═O)R²; —C(═W)R²; —C(═O)OH;—C(═W)OH; —C(═O)ORW; —C(—W)OR²; —C(═O)—SH; —C(═W)SH; —C(═O)SR²;—C(═W)SR²; —C(═O)NH₂; —C(═W)NH₂; —C(═O)NHR²; —C(═W)NHR²; —C(═O)NR²R³;—C(═W)—NR²R³, —C(═W)NH(CH₂)_(p)-(amino acid), a residue of an amino acidor —(CH₂)_(p)(amino acid); wherein if R^(5′) is hydrogen, F, Cl, Br,—NO₂, —CN, —OR², —NR²R², —NHSO₂—C₁₋₃alkyl or —NHCO—C₁₋₃alkyl, then atleast one of R^(4′), R^(6′) and R^(7′) is not hydrogen or alternatively,wherein at least two of R^(4′), R^(5′),R^(6′), R^(7′) are not hydrogen;(c) Z is optionally substituted or unsubstituted acyl, —C(═O)NH₂;—C(═W)—NH₂; —C(═O)NHR²; —C(═W)NHR²; —C(═O)NR²R³; —C(═W)NR²R³;—C(═W)NH(CH₂)_(p)-(amino acid); a residue of an amino acid,—(CH₂)_(p)-(amino acid); —C(═O)R³; —C(═O)H; —C(═W)H; —C(═O)R²; —C(═W)R²;—C(═O)OR³; —C(═O)OH; —C(═W)OH; —C(═O)OR²; —C(═W)—OR²; —C(═O)—SH;—C(═W)SH; —C(═O)SR²; —C(═W)SR²; optionally substituted or unsubstitutedbranched or unbranched alkyl, alkenyl or alkynyl (such as an optionallysubstituted or unsubstituted branched or unbranched C₁₋₆alkyl,C₂₋₆alkenyl or C₂₋₆alkynyl, and in particular CH₃, CF₃, vinyl bromide,—CR²R²—S(O)_(n)—R³, —CR²R²NH₂, —CR²R²NHR², —CR²R²NR²R³ and—CR²R²—C(═O)R²); —CN, or halo (F, Cl, Br or I); (d) Y is O, S orS(O)_(n); (e) each W is independently O, S, —NH₂, —NHR², —NR²R², —N—CN,—N—NH₂, —N—NHR², —N—NR²R³, —N—OH or —N—OR²; (f) each R² is independentlyhydrogen or an optionally substituted or unsubstituted branched orunbranched lower alkyl, alkenyl or alkynyl (such as an optionallysubstituted or unsubstituted branched or unbranched C₁-₃alkyl,C₂₋₄alkenyl or C₂₋₄alkynyl, and in particular CH₃, CF₃, vinyl bromide,—CR²R²—S(O)_(n)—R³, —CR²R²NH₂, —CR²R²NHR², —CR²R²NR²R³ and—CR²R²—C(═O)R²); (g) each R³ is independently hydrogen; optionallysubstituted or unsubstituted branched or unbranched alkyl, alkenyl oralkynyl (such as an optionally substituted or unsubstituted branched orunbranched C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl, and in particular CH₃,CF₃, vinyl bromide, —CR²R²—S(O)_(n)—R³, —CR²R²NH₂, —CR²R²NHR²,—CR²R²NR²R³ and —CR²R²—C(═O)R²); optionally substituted or unsubstitutedaryl (such as phenyl); optionally substituted or unsubstitutedheterocycle; optionally substituted or unsubstituted alkylaryl,optionally substituted or unsubstituted alkylhereterocycle, optionallysubstituted or unsubstituted aralkyl, optionally substituted orunsubstituted heterocycle-alkyl; (h) each n is independently 0, 1 or 2;(i) each p is independently 0, 1, 2, 3, 4 or 5; and (j) wherein if oneor more of the optionally substituted branched or unbranched alkyl,alkenyl, alkynyl, lower alkyl, lower alkenyl or lower alkynyl; acyl;aryl; heterocycle; alkaryl; alkheterocycle; arylalkyl oralkylheterocycle substitutents is substituted, then preferably it issubstituted with one or more of halogen (F, Cl, Br or I), —OH, —OR²,—SH, —SR², oxime (defined herein as —CH═N—OH), hydrazine (defined hereinas —NH—NH₂), —C(═O)H, —C(═W)H, —C(═O)R², —C(═W)R², —C(═O)OH, —C(═W)OH,—C(═O)OH, —C(═W)OR², —C(═O)SH, —C(═W)SH, —C(═O)SR², —C(═W)SR²,—C(═O)NH₂, —C(═W)NH₂, —C(═O)—NHR², —C(═W)NHR², —C(═O)NR²R³,—C(═W)—NR²R³, —NH₂, —NHR², —NR²R², —NHSO₂—C₁₋₃alkyl, —NR²SO₂—C₁-₃alkyl,—NHCO—C₁₋₃alkyl, —NR²CO—C₁₋₃alkyl, —S(O)_(n)—R³, C₁₋₃ alkoxy,C₁₋₃thioether, a residue of an amino acid such as —NH(CH₂)_(p)-(aminoacid) or —C(═W)NH(CH₂)_(p)-(amino acid).
 2. The compound of claim 1,wherein Y is SO₂.
 3. The compound of claim 1, wherein Z is an amide. 4.The compound of claim 1, wherein R¹ is hydrogen.
 5. The compound ofclaim 1, wherein (a) R¹ is hydrogen; (b) R^(4′), R^(5′), R^(6′) andR^(7′) are independently hydrogen, halogen (F, Cl, Br or I), —NO₂, —CN,—OR², —NR²R², —NHSO₂—C₁₋₃alkyl, —NHCO—C₁₋₃alkyl, oxime, hydrazine, orC₁₋₃ alkyl or alkenyl optionally substituted with one or more of —OH,—SH, —C(O)H, —COOH, halogen (F, Cl, Br or I), —NR²R², —C₁₋₃ alkoxy or—C₁₋₃ thioether; wherein if R^(5′) is hydrogen, F, Cl, Br, —NO₂, —CN,—OR², —NR²R², —NHSO₂—C₁₋₃alkyl or —NHCO—C₁₋₃alkyl, then at least one ofR^(4′), R^(6′) and R^(7′) is not hydrogen; (c) R^(2″), R^(3″), R^(4″),R^(5″) and R^(6″) are independently hydrogen, halogen (F, Cl, Br or I),—NO₂, —CN, —OH, —OR², —NR²R², —NHSO₂—C₁₋₃alkyl, —NHCO—C₁₋₃alkyl, —C₁₋₅alkoxy, oxime, hydrazine, —C₁₋₅ alkyl or alkenyl optionally substitutedwith one or more of —OH, —SH, —C(O)H, —COOH, halogen (F, Cl, Br or I),—NR²R², —C₁₋₅ thioether or —C₁₋₅ alkoxy; (d) Z is —CN, —C(═W)NR²R³,—C(═O)R³, —C(═O)OR³, —CR²R²—S(O)_(n)—R³, —CR²R²NHR², —CR²R²—CO—R³ orsubstituted or unsubstituted lower alkyl; (e) Y is O, S, or S(O)_(m);(f) each W is independently O, S, —N—CN or —N—OR²; (g) R² is hydrogen orC₁₋₃ alkyl; (h) R³ is hydrogen, substituted or unsubstituted alkyl,alkenyl, aryl, or heterocycle, —C₁₋₅ alkoxy, —OH, —NR²R², or—(CH₂)_(p)C(O)NR²R², (i) each n is independently 0, 1 or 2; and (j) eachp is independently 0, 1, 2, 3, 4, or
 5. 6. The compound of claim 1,wherein (a) R¹ is hydrogen; (b) R^(4′), R^(5′), R^(6′), R^(7′), areindependently hydrogen, halogen (F, Cl, Br or I), —NO₂, —CN, —OR²,—NR²R², —NHSO₂—C₁₋₃alkyl, —NHCO—C₁₋₃alkyl, oxime (defined herein as—CH═N—OH), hydrazine (defined herein as —NH—NH₂), or C₁₋₃ alkyl oralkenyl optionally substituted with one or more of —OH, —SH, C(O)H,COOH, halogen, NR²R², C₁₋₃ alkoxy, or C₁₋₃ thioether; wherein if R^(5′)is hydrogen, F, Cl, Br, —NO₂, —CN, —OR², —NR²R², —NHSO₂—C₁₋₃alkyl or—NHCO—C₁₋₃alkyl, then at least one of R^(4′), R^(6′) and R^(7′) is nothydrogen; (c) R^(2″), R^(3″), R^(4″), R^(5″), and R^(6″), areindependently hydrogen, halogen (F, Cl, Br or I), —NO₂, —CN, —OR²,—NHSO₂—C₁₋₃alkyl, —NHCO—C₁₋₃alkyl, oxime, hydrazine, —C₁₋₅ alkyl oralkenyl optionally substituted with one or more of —OH, —SH, C(O)H,COOH, halogen, NR²R², C₁₋₅ thioether, or C₁₋₅ alkoxy, —C₁₋₅ alkoxy, —OH,or —NR²R²; (d) Z is —C(W)NR²R³, or —COR³; (e) Y is —S(O)_(n)— or —O—, inwhich n is 0, 1 or 2; (f) W is O, S, —N—CN or —N—OR²; (g) R² is hydrogenor C₁₋₃ alkyl; (h) R³ is C₁₋₅ alkyl, C₁₋₅ alkenyl, aryl, or heterocycle,substituted with one or more of C(O)NR²R², —NR²R², —(CH₂)_(m)C(O)NR²R²,—(CH₂)_(m)C(═W)—NH(CH₂)_(p)-(amino acid); (i) each n is independently 0,1 or 2; and (j) each p is independently 0, 1, 2, 3, 4, or
 5. 7. Acompound of the formula

or a pharmaceutically acceptable salt thereof.
 8. A compound of theformula

or a pharmaceutically acceptable salt thereof.
 9. A compound of theformula

or a pharmaceutically acceptable salt thereof.
 10. A compound of theformula

or a pharmaceutically acceptable salt thereof.
 11. A compound of theformula

or a pharmaceutically acceptable salt thereof.
 12. A compound of theformula

or a pharmaceutically acceptable salt thereof.
 13. A compound of theformula

or a pharmaceutically acceptable salt thereof.
 14. A compound of theformula

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising an effective anti-HIV treatment amount of acompound of claim 1, or its pharmaceutically acceptable salt thereof,together with a pharmaceutically acceptable carrier or diluent.
 16. Apharmaceutical composition comprising an effective anti-HIV treatmentamount of a compound of claim 1, or its pharmaceutically acceptable saltthereof, in combination with one or more other anti-HIV agent,optionally with a pharmaceutically acceptable carrier or diluent. 17.The pharmaceutical composition of claim 16, wherein the other anti-HIVagent is a reverse transcriptase inhibitor.
 18. The pharmaceuticalcomposition of claim 17, wherein the reverse transcriptase inhibitorinduces a mutation lysine 103→asparagine and/or tyrosine 181→cysteine inHIV reverse transcriptase.
 19. A method for the treatment or prophylaxisof an HIV-infection in a host comprising administering to said host aneffective anti-HIV treatment amount of a compound of claim 1, or itspharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier or diluent.
 20. A method for thetreatment or prophylaxis of an HIV-infection in a host comprisingadministering to said host an effective anti-HIV treatment amount of acompound of claim 1, or its pharmaceutically acceptable salt thereof, incombination and/or alternation with one or more other anti-HIV agent,optionally in a pharmaceutically acceptable carrier or diluent.
 21. Themethod of claim 20, wherein the other anti-HIV agent is a reversetranscriptase inhibitor.
 22. The method of claim 21, wherein the reversetranscriptase inhibitor induces a mutation lysine 103→asparagine and/ortyrosine 181→cysteine in HIV reverse transcriptase.
 23. A method for thetreatment or prophylaxis of an HIV-infection in a host, wherein the HIVhas a mutation at lysine 103→asparagine and/or tyrosine 181→cysteine inHIV reverse transcriptase, comprising administering to said host aneffective anti-HIV treatment amount of a compound of claim 1, or itspharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier or diluent.
 24. A method for thetreatment or prophylaxis of an HIV-infection in a host, wherein the HIVis resistant to one or more reverse transcriptase inhibitor(s),comprising administering to said host an effective anti-HIV treatmentamount of a compound of claim 1, or its pharmaceutically acceptable saltthereof, in combination and/or alternation with one or more otheranti-HIV agent, optionally in a pharmaceutically acceptable carrier ordiluent.
 25. A method for salvage therapy in the treatment orprophylaxis of an HIV-infection in a host, comprising administering tosaid host an effective anti-HIV treatment amount of a compound of claim1, or its pharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier or diluent.
 26. A method for salvagetherapy in the treatment or prophylaxis of an HIV-infection in a host,comprising administering to said host an effective anti-HIV treatmentamount of a compound of claim 1, or its pharmaceutically acceptable saltthereof, in combination and/or alternation with one or more otheranti-HIV agent, optionally in a pharmaceutically acceptable carrier ordiluent.
 27. A method for the treatment or prophylaxis of anHIV-infection in a host, wherein the HIV is resistant to one or morereverse transcriptase inhibitor(s), comprising administering to saidhost an effective anti-HIV treatment amount of a compound of claim 1, orits pharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier or diluent.
 28. A method for thetreatment or prophylaxis of an HIV-infection in a host, wherein the HIVhas a mutation at lysine 103→asparagine and/or tyrosine 181→cysteine inHIV reverse transcriptase, comprising administering to said host aneffective anti-HIV treatment amount of a compound of claim 1, or itspharmaceutically acceptable salt thereof, in combination and/oralternation with one or more other anti-HIV agent, optionally in apharmaceutically acceptable carrier or diluent.
 29. The method of anyone of claims 19-28 wherein the host is a human.